4-aryl substituted indolinones

ABSTRACT

The present invention relates to 4-arylindolinones, as well as pharmaceutical compositions thereof, capable of modulating protein kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation. The present invention also relates to methods for treating protein kinase related disorders.

[0001] This application relates to provisional application serialNo.60/256,479, the entire contents of which are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

[0002] The following is offered as background information only and isnot admitted to be prior art to the present invention.

[0003] Protein kinases (“PKs”) are enzymes that catalyze thephosphorylation of hydroxy groups on tyrosine, serine and threonineresidues of proteins. The consequences of this seemingly simple activityare staggering; cell growth, differentiation and proliferation, i.e.,virtually all aspects of cell life in one way or another depend on PKactivity. Furthermore, abnormal PK activity has been related to a hostof disorders, ranging from relatively non-life threatening diseases suchas psoriasis to extremely virulent diseases such as glioblastoma (braincancer).

[0004] The PKs can be conveniently broken down into two classes, theprotein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs).

[0005] One of the prime aspects of PTK activity is their involvementwith growth factor receptors. Growth factor receptors are cell-surfaceproteins. When bound by a growth factor ligand, growth factor receptorsare converted to an active form which interacts with proteins on theinner surface of a cell membrane. This leads to phosphorylation ontyrosine residues of the receptor and other proteins and to theformation inside the cell of complexes with a variety of cytoplasmicsignaling molecules that, in turn, effect numerous cellular responsessuch as cell division (proliferation), cell differentiation, cellgrowth, expression of metabolic effects to the extracellularmicroenvironment, etc. For a more complete discussion, see Schlessingerand Ullrich, Neuron 9:303-391 (1992), which is incorporated byreference, including any drawings, as if fully set forth herein.

[0006] Growth factor receptors with PTK activity are known as receptortyrosine kinases (“RTKs”). They comprise a large family of transmembranereceptors with diverse biological activity. At present, at leastnineteen (19) distinct subfamilies of RTKs have been identified. Anexample of these is the subfamily designated the “HER” RTKs, whichinclude EGFR (epithelial growth factor receptor), HEP2, HER3 and HER4.These RTKs consist of an extracellular glycosylated ligand bindingdomain, a transmembrane domain and an intracellular cytoplasmiccatalytic domain that can phosphorylate tyrosine residues on proteins.

[0007] Another RTK subfamily consists of insulin receptor (IR),insulin-like growth factor I receptor (IGF-IR) and insulin receptorrelated receptor (IRR). IR and IGF-IR interact with insulin, IGF-I andIGF-II to form a heterotetramer of two entirely extracellularglycosylated a subunits and two β subunits which cross the cell membraneand which contain the tyrosine kinase domain.

[0008] A third RTK subfamily is referred to as the platelet derivedgrowth factor receptor (“PDGFR”) group, which includes PDGFRα, PDGFRβ,CSFIR, c-kit and c-fms. These receptors consist of glycosylatedextracellular domains composed of variable numbers of immunoglobin-likeloops and an intracellular domain wherein the tyrosine kinase domain isinterrupted by unrelated amino acid sequences.

[0009] Another group which, because of its similarity to the PDGFRsubfamily, is sometimes subsumed into the later group is the fetus liverkinase (“flk”) receptor subfamily. This group is believed to be made ofup of kinase insert domain-receptor fetal liver kinase-l (KDRIFLK-I),flk-IR, flk-4 and fms-like tyrosine kinase I (flt-1).

[0010] A further member of the tyrosine kinase growth factor receptorfamily is the fibroblast growth factor (“FGF”) receptor subgroup. Thisgroup consists of four receptors, FGFR1-4, and seven ligands, FGF1-7.While not yet well defined, it appears that the receptors consist of aglycosylated extracellular domain containing a variable number ofimmunoglobin-like loops and an intracellular domain in which thetyrosine kinase sequence is interrupted by regions of unrelated aminoacid sequences.

[0011] Still another member of the tyrosine kinase growth factorreceptor family is the vascular endothelial growth factor (“VEGF”)receptor subgroup. VEGF is a dimeric glycoprotein similar to PDGF buthas different biological functions and target cell specificity in vivo.In particular, VEGF is presently thought to play an essential role isvasculogenesis and angiogenesis.

[0012] Still another member of the tyrosine kinase growth factorreceptor family is MET, often referred to as c-Met. c-Met is thought toplay a role in priimary tumor growth and metastasis.

[0013] A more complete listing of the known RTK subfamilies is describedin Plowman et al., DN&P, 7(6):334-339 (1994), which is incorporated byreference, including any drawings, as if fully set forth herein.

[0014] In addition to the RTKs, there also exists a family of entirelyintracellular PTKs called “non-receptor tyrosine kinases” or “cellulartyrosine kinases.” This latter designation, abbreviated “CTK,” will beused herein. CTKs do not contain extracellular and transmembranedomains. At present, over 24 CTKs in 11 subfamilies (Src, Frk, Btk, Csk,Abl, Zap70, Fes, Fps, Fak, Jak and Ack) have been identified. The Srcsubfamily appear so far to be the largest group of CTKs and includesSrc, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. For a more detaileddiscussion of CTKs, see Bolen, Oncogene, 8:2025-2031 (1993), which isincorporated by reference, including any drawings, as if fully set forthherein.

[0015] The serine/threonine kinases, STKs, like the CTKs, arepredominantly intracellular although there are a few receptor kinases ofthe STK type. STKs are the most common of the cytosolic kinases; i.e.,kinases that perform their function in that part of the cytoplasm otherthan the cytoplasmic organelles and cytoskelton. The cytosol is theregion within the cell where much of the cell's intermediary metabolicand biosynthetic activity occurs; e.g., it is in the cytosol thatproteins are synthesized on ribosomes.

[0016] RTKs, CTKs and STKs have all been implicated in a host ofpathogenic conditions including, significantly, cancer. Other pathogenicconditions which have been associated with PTKs include, withoutlimitation, psoriasis, hepatic cirrhosis, diabetes, angiogenesis,restenosis, ocular diseases, rheumatoid arthritis and other inflammatorydisorders, immunological disorders such as autoimmune disease,cardiovascular disease such as atherosclerosis and a variety of renaldisorders.

[0017] With regard to cancer, two of the major hypotheses advanced toexplain the excessive cellular proliferation that drives tumordevelopment relate to functions known to be PK regulated. That is, ithas been suggested that malignant cell growth results from a breakdownin the mechanisms that control cell division and/or differentiation. Ithas been shown that the protein products of a number of proto-oncogenesare involved in the signal transduction pathways that regulate cellgrowth and differentiation. These protein products of proto-oncogenesinclude the extracellular growth factors, transmembrane growth factorPTK receptors (RTKs), cytoplasmic PTKs (CTKs) and cytosolic STKs,discussed above.

[0018] In view of the apparent link between PK-related cellularactivities and wide variety of human disorders, it is no surprise that agreat deal of effort is being expended in an attempt to identify ways tomodulate PK activity. Some of these have involved biomimetic approachesusing large molecules patterned on those involved in the actual cellularprocesses (e.g., mutant ligands (U.S. application Ser. No. 4,966,849);soluble receptors and antibodies (Application No. WO 94/10202, Kendalland Thomas, Proc. Nat'l Acad. Sci., 90:10705-10709 (1994), Kim, et al.,Nature, 362:841-844 (1993)); RNA ligands (Jelinek, et al., Biochemistry,33:10450-56); Takano, et al., Mol. Bio. Cell, 4:358A (1993); Kinsella,et al., Exp. Cell Res., 199:56-62 (1992); Wright, et al., J CellularPhys., 152:448-57) and tyrosine kinase inhibitors (WO 94/03427; WO92/21660; WO 91/15495; WO 94/14808; U.S. Pat. No. 5,330,992; Mariani, etal., Proc. Am. Assoc. Cancer Res., 35:2268 (1994)).

[0019] In addition to the above, attempts have been made to identifysmall molecules which act as PK inhibitors. For example, bis-monocylic,bicyclic and heterocyclic aryl compounds (PCT WO 92/20642),vinylene-azaindole derivatives (PCT WO 94/14808) and1-cyclopropyl-4-pyridylquinolones (U.S. Pat. No. 5,330,992) have beendescribed as tyrosine kinase inhibitors. Styryl compounds (U.S. Pat. No.5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No.5,302,606), quinazoline derivatives (EP Application No. 0 566 266 A1),selenaindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxyliccompounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO91/15495) have all been described as PTK inhibitors useful in thetreatment of cancer.

SUMMARY OF THE INVENTION

[0020] A family of novel pyrrole-substituted 2-indolinone compounds havebeen discovered which exhibit PK modulating ability and have a salutaryeffect against disorders related to abnormal PK activity (U.S. Pat. No.5,792,783; U.S. application Ser. No. 09/322,297). It has beendemonstrated that this family of compounds modulates the catalyticactivity of receptor tyrosine kinases (RTKs), non-receptor proteintyrosine kinases (CTKs) and serine/threonine protein kinases (STKs).

[0021] For example, the catalytic activity of RTKs such as, withoutlimitation, EGF, MET, HER2, HER3, HER4, IR, IGF-IR, IRR, PDGFRct,PDGFRO, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR/Flk-1, Flt-1, FGFR-1 R,FGFR-2R, FGFR-3R and FGFR-4R may be modulated with pyrrole-substituted2-indolinone compounds, in particular Met may be modulated. By affectingthe catalytic activity of RTKs, CTKs and/or STKs, such compounds caninterfere with the signals transduced by such proteins. This applicationalso encompasses affecting the catalytic activity of protein kinasesdisclosed in U.S. application Ser. Nos. 09/233,857; 09/291,417;60/149,005 and 60/136,503, and PCT Application No. PCT/US99/13533, theentire disclosures of which are hereby incorporated by reference.

[0022] 1. CHEMISTRY

[0023] In one aspect, the present invention relates to compounds haivngthe following chemical structure (Formula I).

[0024] wherein:

[0025] R¹ is an aryl or heteroaryl substituent, optionally substitutedby one or more substituent selected from the group consisting ofhalogen, —OR⁶, —COR⁶, —COOR⁶, —OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷,—CN,—NO₂, —CX₃, —SR⁶, —SOR⁶, —SO₂R⁶, —SO₂ 0R⁶, —SO₂NR⁶R⁷, —RNSO₂R⁷,perfluoroalkyl, lower alkyl, lower alkyl further substituted by one ormore of R2, lower alkenyl,y lower alkenyl further substituted by one ormore of R^(2,) lower alkynyl, lower alkynyl further substituted by oneor more of R², cycloalkyl, cycloalkyl further substituted by one or moreof R², a heterocyclic ring, a heterocyclic ring further substituted byone or more of R², aryl and aryl further substituted by one or more ofR²;

[0026] R² is selected from the group consisting of hydrogen, halogen,—OR⁶, —COR⁶, —COOR⁶, —OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷, —CN, —NO₂,—CX₃, —SR⁶, —SOR⁶, —SO₂R⁶, —SO20R⁶, —SO₂NR⁶R⁷, —RNSO₂R⁷, perfluoroalkyl,lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, a heterocyclicring and aryl;

[0027] R³ is selected from the group consisting of hydrogen, halogen,—OR⁶, —COR⁶, —COOR⁶ , —OCOR⁶ , —CONR⁶R⁷ , —R⁶NCOR⁷ , —NR⁶R⁷, —CN, —NO₂,—CX₃, —SR⁶, —SOR⁶, —SO₂R⁶, —SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷,perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aheterocyclic ring, a heterocyclic ring further substituted by one ormore of R², and aryl, wherein said lower alkyl is further substituted by—CONR⁶R⁷, NR⁶R⁷, —SO₂R⁶, —R⁶NSO₂R, or —SO₂NR⁶R ⁷;

[0028] R⁴ is selected from the group consisting of hydrogen, halogen,—OR⁶, —COR⁶, —COOR⁶, —OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷ , —NR⁶R⁷, —CN, —NO₂,—CX₃, —SR⁶, SOR⁶, —SO₂R⁶, —SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷, perfluoroalkyl,lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, a heterocyclicring and aryl, wherein said lower alkyl is further substituted by—CONR⁶R⁷, NR⁶R⁷, —SO₂R⁶, —R⁶NSO₂R, or SO₂NR⁶R⁷;

[0029] R⁵ is selected from the group consisting of hydrogen, halogen,—OR⁶, —COR⁶, —COOR⁶, —OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷, —CN, —NO₂,—CX₃, —SR⁶, —SOR⁶, —SO₂R⁶, —SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷,perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aheterocyclic ring and aryl;

[0030] provided that no more than one of R³, R⁴, or R⁵ is hydrogen;

[0031] R³ and R⁴ or R⁴ and R⁵ may be linked together to form a 4-, 5-,6- or 7- membered ring optionally containing one or more hetero atomsselected from the group consisting of O, N, S, SO and SO₂, which maycontain 1 or 2 double bonds and may be further substituted by one ormore of —(CH₂)_(n)NR⁶R⁷, —(CH₂)_(n)—CR⁶R⁷,—(CH₂)_(n)—C(O)—(CH₂)_(n)—NR⁶R⁷, —(CH₂)_(n)SO₂R⁶R⁷, —(CH₂)_(n)NSO₂R⁶R⁷or —(CH₂),—C(O)—R⁶, wherein n is 0-4;

[0032] R⁶ and R⁷ are independently selected from the group consisting ofhydrogen, —CX₃, perfluoroalkyl, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, a heterocyclic ring and aryl;

[0033] wherein lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,the heteocyclic ring or aryl may be further substituted by one or moreof (i) —NR ¹²R¹³, (ii) hydroxy, (iii) halo, (iv) a heterocyclic ring,(v) lower alkyl, (vi) —C(O)—NR¹²R¹³, (vii) —OR¹², (viii) —SO₂R¹²R¹³, or(ix) —COR⁶;

[0034] wherein said heterocyclic ring (iv) may be further substituted byone or more of lower alkyl, —COR ¹², —NR¹²COR¹³, halogen, —OR¹², CX₃,—C(O)NR¹²R¹³, —SO₂R¹²R¹³, or —SO₂NR¹²R¹³,

[0035] or R⁶ and R⁷ may be linked together to form a 4, 5- or 6-membered ring, optionally containing a hetero atom selected from thegroup consisting of N, 0, S and SO₂, which may be further substituted by—CONR¹²R, lower alkyl, hydroxy, —(CH₂)_(n)—NR¹²R ¹³,—(CH₂)₁-heterocycle, —(CH₂)_(n)—C(O)—NR¹²R¹³, —(CH₂)_(n)SO₂R¹² R¹³, or—(CH₂)_(n)NSO₁₂R¹²R ¹³, wherein said heterocycle may be furthersubstituted by halo, lower alkyl, —COR ¹², hydroxy, —C(O)—NR¹²R¹³,—OR¹², —SO₂R¹²R¹³, or —SO₂NR¹²R¹³;

[0036] X is fluorine, chlorine, bromine or iodine;

[0037] R¹² is selected from the group consisting of hydrogen, —CX₃,perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl,—(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)-heterocycle, and aryl;

[0038] R¹³ is selected from the group consisting of hydrogen, —CX₃,perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl,—(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)-heterocycle, and aryl;

[0039] or R¹² and R¹³ may be linked together to form a 4-, 5- or 6-membered ring optionally containing one or more hetero atoms selectedfrom the group consisting of O, N, S, SO and SO², which may contain 1 or2 double bonds;

[0040] or a pharmaceutically acceptable salt thereof.

[0041] Compounds—Preferred Structural Features

[0042] In a preferred aspect, R³ and R⁴ or R⁴ and R⁵ may be linkedtogether to form a ring.

[0043] In a particularly preferred aspect, R³ and R⁴ or R⁴ and R⁵ arelinked together to form a ring, the ring together with pyrrole isselected from the group consisting of:

[0044] In another preferred aspect, R³ may be excluded when both R⁴ andR⁵ are hydrogen. In still a further preferred aspect, R¹ is aryl.

[0045] A preferred aspect of the invention relates to compounds ofFormula II

[0046] wherein each R⁸ is independently halogen, —OR⁶, —COR⁶, —COOR⁶,OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷, —CN, —NO₂, —CX₃, —SR⁶, SOR⁶, —SO₂R⁶,—SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R^(7,) perfluoroalkyl, lower alkyl, loweralkyl further substituted by one or more of R², lower alkenyl, loweralkenyl further substituted by one or more of R², lower alkynyl, loweralkynyl further substituted by one or more of R², cycloalkyl, cycloalkylfurther substituted by one or more of R², a heterocyclic ring, aheterocylic ring further substituted by one or more of R^(2,) aryl andaryl further substituted by one or more of R²;

[0047] R² is selected from the group consisting of hydrogen, halogen,—OR⁶, —COR⁶, —COOR⁶, OCOR⁶, —CONR⁶R⁷, —R¹²NCOR¹³, —NR⁶R⁷, —R⁶NC(O)R⁷,—CN, —NO₂, —CX₃, —SR⁶, —SOR⁶, —SO₂R⁶,—SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷,perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aheterocyclic ring and aryl;

[0048] R⁶ and R⁷ are independently selected from the group consisting ofhydrogen, —CX₃, perfluoroalkyl, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, a heterocyclic ring and aryl;

[0049] wherein lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,the heteocyclic ring or aryl may be further substituted by one or moreof (i) —NR¹²R¹³, (ii) hydroxy, (iii) halo, (iv) a heterocyclic ring, (v)lower alkyl, (vi) —C(O)—NR¹²R¹³, (vii) —OR¹², (viii) —SO₂R¹²R¹³, or (ix)—COR⁶;

[0050] wherein said heterocyclic ring (iv) may be further substituted byone or more of lower alkyl, —COR¹², —NR¹²COR¹³, halogen, —OR¹², CX₃,—C(O)NRR¹²R¹³, —SO₂R¹²R¹³, or —SO₂NR¹²R¹³,

[0051] or R⁶ and R⁷ may be linked together to form a 4, 5- or 6-membered ring, optionally containing a hetero atom selected from thegroup consisting of N, O, S and SO₂, which may be further substituted by—CONR¹²R¹³, lower alkyl, hydroxy, —(CH₂)_(n)—NR¹²R¹³,—CH₂)_(n)-heterocycle, —(CH₂)_(n)—C(O)—NR¹²R¹³, —(CH₂)_(n)SO₂R¹²R¹³, or—(CH₂)_(n)NSO₂R¹²R¹³, wherein said heterocycle may be furthersubstituted by halo, lower alkyl, —COR ¹², hydroxy, —C(O)—NR¹²R¹³,—OR¹², —SO₂R¹²R¹³, or —SO₂NR¹²R¹³;

[0052] X is fluorine, chlorine, bromine or iodine;

[0053] R¹² is selected from the group consisting of hydrogen, —CX₃,perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl,—(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)-heterocycle, and aryl;

[0054] R¹³ is selected from the group consisting of hydrogen, —CX₃,perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl,—(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)-heterocycle, and aryl;

[0055] or R¹² and R¹³ may be linked together to form a 4-, 5- or 6-membered ring optionally containing one or more hetero atoms selectedfrom the group consisting of O, N, S, SO and SO₂, which may contain 1 or2 double bonds and may be further substituted by halogen, —OR⁶, —COR⁶,—COOR⁶, OCOR⁶, —CONR⁶R⁷, —R¹²NCOR¹³, —NR⁶R⁷, —R⁶NC(O)R⁷, —CN, —NO₂,—CX₃, —SR⁶, SOR⁶, —SO₂R⁶,—SO₂R⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷, perfluoroalkyl,lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, a heterocyclicring and aryl;

[0056] R⁹ is selected from the group consisting of halogen, —CX₃, loweralkyl, cycloalkyl, a heterocyclic ring and aryl, each of which may befurther substituted by halogen, —OR⁶, —COOR⁶, —OCOR⁶, —CONR⁶R⁷,—R⁶NCOR⁷, —NR⁶R⁷, —CX₃, —SR⁶, SOR⁶, SO₂R⁶, —SO₂OR⁶, SO₂NR⁶R⁷, or—R⁶NSO₂R⁷; and

[0057] m is 1 or 2,

[0058] or a pharmaceutically acceptable salt thereof.

[0059] Another preferred aspect of the invention relates to compounds ofFormula III,

[0060] wherein each R⁸ is independently halogen, —OR⁶, —COR⁶, —COOR⁶,OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷, —CN, —NO₂, —CX₃, —SR⁶, —SO₂R⁶,—SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷, perfluoroalkyl, lower alkyl, lower alkylfurther substituted by one or more of R , lower alkenyl, lower alkenylfurther substituted by one or more of R², lower alkynyl, lower alkynylfurther substituted by one or more of R², cycloalkyl, cycloalkyl furthersubstituted by one or more of R², a heterocyclic ring, a heterocyclicring further substituted by one or more of R², aryl and aryl furthersubstituted by one or more of R²;

[0061] R² is selected from the group consisting of hydrogen, halogen,—OR⁶, —COR⁶, —COOR⁶, OCOR⁶, —CONR⁶R ⁷ , —R⁶NCOR ⁷, —NR⁶R ⁷, —CN, —NO₂,—CX₃, —SO₂R⁶, —SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷, perfluoroalkyl, loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, a heterocyclic ring andaryl;

[0062] R⁶ and R⁷ are independently selected from the group consisting ofhydrogen, —CX₃, perfluoroalkyl, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, a heterocyclic ring and aryl;

[0063] wherein lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,the heteocyclic ring or aryl may be further substituted by one or moreof (i) —NR¹²R¹³, (ii) hydroxy, (iii) halo, (iv) a heterocyclic ring, (v)lower alkyl, (vi) —C(O)NR¹²R¹³, (vii) —OR¹², (viii) —SO₂R¹²R¹³, or (ix)—COR⁶;

[0064] wherein said heterocyclic ring (iv) may be further substituted byone or more of lower alkyl, —COR¹², —NR¹²COR¹³, halogen, —OR¹², CX₃,—C(O)NR¹²R ¹³, —SO₂R¹²R¹³, or —SO₂NR¹²R¹³;

[0065] or R⁶ and R⁷ may be linked together to form a 4, 5- or 6-membered ring, optionally containing a hetero atom selected from thegroup consisting of N, O, S and SO₂, which may be further substituted by—CONR¹²R¹³, lower alkyl, hydroxy, —(CH₂)_(n)NR¹²R¹³,—(CH₂)_(n)-heterocycle, —(CH₂)_(n)—C(O)—NR¹²R¹³, —(CH₂)_(n)SO₂R¹²R¹³, or—(CH₂)_(n)NSO₂R¹²R¹³, wherein said heterocycle may be furthersubstituted by halo, lower alkyl, —COR ¹², hydroxy, —C(O)—NR¹²R¹³,—OR¹², —SO₂NR¹²R¹³, or —SO₂NR¹²R¹³;

[0066] X is fluorine, chlorine, bromine or iodine;

[0067] R¹⁰ is H, lower alkyl, lower alkyl substituted with one or moreof R², —(CH₂)_(n)NR⁶R⁷, —CONR⁶R⁷, —SO₂NR⁶R⁷, —(CH₂)_(n)—SR⁶,—(CH₂)_(n)—SOR⁶, —(CH₂)_(n)—SO₂R⁶, —(CH₂)_(n)—SO₂NR⁶R⁷, or—(CH₂)_(n)—OR⁶;

[0068] R¹¹ is H, lower alkyl, lower alkyl substituted with one or moreof R², —(CH₂)_(n)NR⁶R⁷, —CONR⁶R⁷, —SO₂NR⁶R⁷, —(CH₂)_(n)—SR⁶,—(CH₂)—(CH₂)_(n)—SOR⁶, —(CH₂)_(n)—SO₂R⁶, —(CH₂)_(n)—SO₂NR⁶R⁷, or—(CH₂)_(n)—OR⁶;

[0069] R¹² is selected from the group consisting of hydrogen, —CX₃,perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl,—(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)-heterocycle, and aryl;

[0070] R¹³ is selected from the group consisting of hydrogen, —CX₃,perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl,—(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)-heterocycle, and aryl;

[0071] or R¹² and R¹³ may be linked together to form a 4-, 5- or 6-membered ring optionally containing one or more hetero atoms selectedfrom the group consisting of O, N, S, SO and SO₂, which may contain 1 or2 double bonds; and

[0072] wherein ---- is a single or double bond; and

[0073] n is 0-4,

[0074] or a pharmaceutically acceptable salt thereof.

[0075] The compounds presented herein are exemplary only and are not tobe construed as limiting the scope of this invention in any manner.

[0076] The chemical formulae referred to herein may exhibit thephenomena of tautomerism and structural isomerism. For example, thecompounds described herein may adopt an E or a Z configuration about thedouble bond connecting the 2-indolinone moiety to the pyrrole moiety orthey may be a mixture of E and Z. This invention encompasses anytautomeric or structural isomeric form and mixtures thereof whichpossess the ability to modulate RTK, CTK and/or STK activity and is notlimited to any one tautomeric or structural isomeric form.

[0077] In addition, the formulae referred to herein may also exhibitstereoisomerism, in which such compounds may adopt an R or Sconfiguration at chiral centers. Thus, this invention also encompassesany stereoisomeric form, their corresponding enantiomers (d- and 1- or(+) and (−) isomers) and diastereomers thereof, and mixtures thereof,which possess the ability to modulate RTK, CTK and/or STK activity andis not limited to any one stereoisomeric form. Table 1 shows thechemical structures of the preferred compounds of the invention. TABLE 1Preferred 4-Aryl Substituted Indolinones Example Structure Name 1

2-Methyl-4-[3-(4-methyl-piperazin-1- yl)-propyl]-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H- pyrrole-3-carboxylic acid ethyl ester2

3-[3,5-Dimethyl-4-(4-methyl- piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro- indol-2-one 3

2,4-Dimethyl-5-(2-oxo-4-phenyl-1,2- dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2- diethylamino-ethyl)-amide 4

3-[3,5-Dimethyl-4-(4-methyl- piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3- dihydro-indol-2-one 5

5-[4-(4-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 6

5-[4-(4-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 7

5-[4-(4-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-ylethyl)-amide8

4-(4-Fluoro-phenyl)-3-[5-methyl-3-(4- methyl piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro- indol-2-one 9

2-[4-(4-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-purrole-3-carboxylic acid (2- [1,2,3]triazol-1-yl-ethyl) amide10

3-[3-((S)-3-Dimethylamino-pyrrolidine- 1-carbonyl)-5-methyl-1H-pyrrol-2-yhnethylene]-4-(4-fluoro-phenyl)-1,3- dihydro indol-2-one 11

3-[3-((R)-3-Dimethylamino-pyrrolidine- 1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3- dihydro indol-2-one 12

3-[3,5-Dimethyl-4-(4-methyl- piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-fluiro-phenyl)-1,3- dihydro-indol-2-one 13

5-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 14

5-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 15

5-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide 16

3-[3-((S)-3-Dimethylamino-pyrrolidine- 1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3- dihydro indol-2-one 17

3-[3-((R)-3-Dimethylamino-pyrrolidine- 1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3- dihydro indol-2-one 18

5-[4-(3-Fluoro-phenyl])-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)- propyl]-1H-pyrrole-3-carboxylicacid ethyl ester 19

3-[3-(cis-3,5-Dimethyl-piperazine-1- carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3- dihydro indol-2-one 20

4-(4-Chloro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H- pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one 21

5-[4-(4-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 22

5-[4-(4-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 23

5-[4-(4-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide 24

4-(4-Chloro-phenyl)-3-[3-((S)-3- dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 25

4-(4-Chloro-phenyl)-3-[3-((R)-3- dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 26

5-[4-(4-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)- propyl]-1H-pyrrole-3-carboxylicacid ethyl ester 27

4-(4-Chloro-phenyl)-3-[3-(cis-3,5- dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 28

4-(3-Chloro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H- pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one 29

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 30

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 31

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide 32

4-(3-Chloro-phenyl)-3-[3-((S)-3- dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 33

4-(3-Chloro-phenyl)-3-[3-((R)-3- dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 34

2-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- [1,2,3]triazol-1-yl-ethyl)-amide35

4-(3-Chloro-phenyl)-3-[3-(cis-3,5- dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 36

3-[3,5-Dimethyl-4-(4-methyl- piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3- dihydro-indol-2-one 37

5-[4-(4-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 38

5-[4-(4-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 39

5-[4-(4-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide 40

3-[4-(cis-3,5-Dimethyl-piperazine-1- carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3- dihydro-indol-2-one 41

2-[4-(4-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- pyrrolidin-1-yl-ethyl)-amide 42

2-[4-(4-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- [1,2,3]triazol-1-yl-ethyl)-amide43

3-[3-((S)-Dimethylamino-pyrrolidine- 1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3- dihydro-indol-2-one 44

3-[3-((R)-3-Dimethylamino-pyrrolidine- 1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3- dihydro-indol-2-one 45

3-[3,5-Dimethyl-4-(4-methyl- piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3- dihydro-indol-2-one 46

5-[4-(3-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 47

5-[4-(3-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 48

5-[4-(3-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide 49

3-[4-(cis-3,5-Dimethyl-piperazine-1- carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)- 1,3-dihydro-indol-2-one 50

2-[4-(3-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- pyrrolidin-1-yl-ethyl)-amide 51

2-[4-(3-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- [1,2,3]triazol-yl-ethyl)-amide52

5-[4-(3-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide53

4-(4-Bromo-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H- pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one 54

5-[4-(4-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 55

5-[4-(4-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 56

5-[4-(4-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide 57

4-(4-Bromo-phenyl)-3-[4-[cis-3,5- dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 58

2-[4-(4-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- pyrrolidin-1-yl-ethyl)-amide 59

2-[4-(4-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- E1,2,3]triazol-1-yl-ethyl)-amide60

5-[4-(4-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide61

5-[4-(4-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- diethylamino-ethyl)-amide 62

3-[3,5-Dimethyl-4-(4-methyl- piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-bromo-phenyl)-1,3- dihydro-indol-2-one 63

5-[4-(3-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 64

5-[4-(3-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 65

5-[4-(3-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide 66

3-[4-(cis-3,5-Dimethyl-piperazine-1- carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-bromo-phenyl)-1,3- dihydro-indol-2-one 67

2-[4-(3-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- pyrrolidin-1-yl-ethyl)-amide 68

2-[4-(3-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazole-1-yl-ethyl)-amide 69

5-[4-(3-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dissopropylamino-ethyl)-amide70

5-[4-(4-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2- diethylamino-ethyl)-amide 71

5-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2- diethylamino-ethyl)-amide 72

5-[4-(4-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2- diethylamino-ethyl)-amide 73

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2- diethylamino-ethyl)-amide 74

5-[4-(4-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2- diethylamino-ethyl)-amide 75

5-[4-(3-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2- diethylamino-ethyl)-amide 76

5-[4-(4-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2- diethylamino-ethyl)-amide 77

5-[4-(3-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrol-2-carboxylic acid (2- diethylamino-ethyl)-amide 78

3-(3,5-Dimethyl-1H-pyrrol-2- ylmethylene)-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one 79

3-(3,5-Dimethyl-1H-pyrrol-2- ylmethylene)-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one 80

3-(3,5-Dimethyl-1H-pyrrol-2- ylmethylene)-4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one 81

3-(3,5-Dimethyl-1H-pyrrol-2- ylmethylene)-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one 82

3-(3,5-Dimethyl-1H-pyrrol-2- ylmethylene)-4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one 83

3-(3,5-Dimethyl-1H-pyrrol-2- ylmethylene)-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one 84

3-(3,5-Dimethyl-1H-pyrrol-2- ylmethylene)-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one 85

3-(3,5-Dimethylamino-1H-pyrrol-2- ylmethylene)-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one 86

5-[4-(4-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- diethylamino-ethyl)-amide 87

5-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- diethylamino-ethyl)-amide 88

5-[4-(4-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- diethylamino-ethyl)-amide 89

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- diethylamino-ethyl)-amide 90

5-[4-(3-bromo-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- diethylamino-ethyl)-amide 91

5-[4-(4-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-dihydroxy-indol-3-ylidenemethyl]-4- methyl-1H-pyrrole-3-carboxylic acid(2- diethylamino-ethyl)-amide 92

5-[4-(3-Methoxy-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- diethylamino-ethyl)-amide 93

3-[3,5-Dimethyl-4-(4-methyl- piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(2-fluoro-phenyl)-1,3- dihydro-indol-2-one 94

5-[4-(2-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 95

5-[4-(2-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 96

5-[4-(2-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide 97

2-[4-(2-fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- diethylamino-ethyl)-amide 98

2-[4-(2-fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- pyrrolidin-1-yl-ethyl)-amide 99

2-[4-(2-fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl[-5-methyl-1H-pyrrole-3-carboxylic acid (2- [1,2,3]triazol-1-yl-ethyl)-amide100

3-[3-(cis-3,5-dimethyl-piperazine-1- carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(2-fluoro-phenyl)-1,3- dihydro-indol-2-one 101

5-[4-(4-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide 102

2-[4-(4-fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3- pyrrolidin-1-yl-propyl)-amide103

5-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide 104

3-[3,5-Dimethyl-4-(4-methyl- dihydro-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl- phenyl)-1,3-dihydro-indol-2-one 105

2,4-Dimethyl-5-[2-oxo-4-(3- trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3- carboxylic acid(2-diethylamino-ethyl)- amide 106

2,4-Dimethyl-5-[2-oxo-4-(3- trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3- carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 107

2,4-Dimethyl-5-[2-oxo-4-(3- trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3- carboxylic acid(2-[1,2,3]triazol-1-yl- ethyl)-amide 108

5-methyl-2-[2-oxo-4-(3-trifluoromethyl- phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-oyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide109

5-methyl-2-[2-oxo-4-(3-trilfuooromethyl- phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide 110

5-methyl-2-[2-oxo-4-(3-trifluoromethyl- phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid(2-]1,2,3]triazol-1-yl-ethyl)-amide 111

3-[3-(cis-3,5-dimethyl-piperazine-1- carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(2-trifluoromethyl- phenyl)-1,3-dihydro-indol-2-one 112

2,4-Dimethyl-5-[2-oxo-4-(3- trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3- carboxylic acid(3-diethylamino-propyl)- amide 113

5-methyl-2-[2-oxo-4-(3-trilfuoromethyl- p-henyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid(3-pyrrolidin-1-yl-propyl)-amide 114

3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro indol-2-one 115

3-[3-Methyl-4-(cis-3,5-dimethyl- piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl- phenyl)-1,3-dihydro-indol-2-one 116

4-(3-chloro-4-fluoro-phenyl)-3-[3,5- dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]- 1,3-dihydro-indol-2-one 117

5-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide 118

5-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide 119

2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylicacid(2- pyrrolidin-1-yl-ethyl)-amide 120

2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylicacid (2- [1,2,3]triazol-1-yl-ethyl)-amide 121

2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylicacid (3- pyrrolidin-1-yl-propyl)-amide 122

4-(4-chloro-phenyl)-3-[3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 123

4-(2-fluoro-phenyl)-3-[3-methyl-4-(4- methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro- indol-2-one 124

4-(4-fluoro-phenyl)-3-[3-methyl-4-(4- methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro- indol-2-one 125

4-(4-chloro-phenyl)-3-[3-methyl-4-(4- methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro- indol-2-one 126

4-(4-bromo-phenyl)-3-[3-methyl-4-(4- methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro- indol-2-one 127

4-(3-bromo-phenyl)-3-[3-methyl-4-(4- methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro- indol-2-one 128

4-(4-methoxy-phenyl)-3-[3-methyl-4-(4- methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro- indol-2-one 129

4-(3-methoxy-phenyl)-3-[3-methyl-4-(4- methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro- indol-2-one 130

3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4- phenyl-1,3-dihydro-indol-2-one 131

3-[4-(cis-3,5-dimethyl-piperazine-1- carbonyl)-3-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3- dihydro indol-2-one 132

4-(4-Chloro-phenyl)-3-[4-[cis-3,5- dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrol-2- ylmethylene]-1,3- dihydro-indol-2-one 133

4-(4-Bromo-phenyl)-3-[4-(cis-3,5- dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 134

3-[4-(cis-3,5-dimethyl-piperazine-1- carbonyl)-3-methyl-1H-pyrrol-2-ylmethylene-4-(4-methoxy-phenyl)-1,3- dihydro-indol-2-one 135

3-[4-(cis-3,5-dimethyl-piperazine-1- carbonyl)-3-methyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3- dihydro-indol-2-one 136

3-[4-(cis-3,5-dimethyl-piperazine-1- carbonyl)-3-methyl-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro- indol-2-one 137

4-(4-chloro-phenyl)-3-[4-[3-(cis-3,5-dimethyl-piperazin-1-yl)-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-ylmethylene]- 1,3-dihydro-indol-2-one 138

3-{4-[3-(cis-3,5-Dimethyl-piperazin-1-yl)-3-oxo-propyl]-3,5-dimethyl-1H- pyrrol-2-ylmethylene}-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one 139

3-[3,5-Dimethyl-4-(4-methyl- piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-trifluoromethoxy- phenyl)-1,3-dihydro-indol-2-one 140

2,4-Dimethyl-5-[2-oxo-4-(4- trifluoromethoxyphenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3- carboxylic acid(2-diethylamino-ethyl)- amide 141

2,4-Dimethyl-5-[2-oxo-4-(4- trifluoromethoxy phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3- carboxylic acid (2-[1,2,3]triazol1-yl- ethyl)-amide 142

5-methyl-2-[2-oxo-4-(4- trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3- carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 143

5-methyl-2-[2-oxo-4-(4- trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3- carboxylic acid (2-[1,2,3]triazol1-yl- ethyl)-amide 144

5-methyl-2-[2-oxo-4-(4- trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyyl]-1H-pyrrole-3- carboxylic acid(3-pyrrolidin-1-yl- propyl)-amide 145

3-[3-(trans-3,5-Dimethyl-piperazine-1- carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3- dihydro-indol-2-one 146

4-(4-Chloro-phenyl)-3-[3-(trans-3,5- dimethyl piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 147

4-(3-Chloro-phenyl)-3-[3-(trans-3,5- dimethyl piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 148

3-[4-(trans-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3- dihydro-indol-2-one 149

3-[4-(trans-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3- dihydro-indol-2-one 150

4-(4-Bromo-phenyl)-3-[4-[trans-3,5- dimethyl piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 151

3-[4-(trans-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2- ylmethylene]-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one 152

3-[3-[trans-3,5-dimethyl-piperazine-1- carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(2-fluoro-phenyl)-1,3- dihydro-indol-2-one 153

3-{3-[trans-3,5-dimethyl-piperazine-1- carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene}-4-(2-trifluoromethyl- phenyl)-1,3-dihydro-indol-2-one 154

3-[3-Methyl-4-[trans-3,5-dimethyl- piperazine-1-carbonyl]-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl- phenyl)-1,3-dihydro-indol-2-one 155

3-{4-[trans-3,5-dimethyl-piperazine-1- carbonyl]-3-methyl-1N-pyrrol-2-ylmethylene}-4-(4-fluoro-pjhenyl)-1,3- dihydro-indol-2-one 156

4-(4-Chloro-phenyl)-3-[4-[trans-3,5- dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 157

4-(4-Bromo-phenyl)-3-[4-[trans-3,5- dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3- dihydro-indol-2-one 158

3-{4-[trans-3,5-dimethyl-piperazine-1- carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-methoxy-phenyl)- 1,3-dihydro-indol-2-one 159

3-{4-[trans-3,5-dimethyl-piperazine-1- carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(3-methoxy-phenyl)- 1,3-dihydro-indol-2-one 160

3-{4-[trans-3,5-dimethyl-piperazine-1- carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-phenyl-1,3-dihydro- indol-2-one 161

4-(4-chloro-phenyl)-3-{4-{3-[trans-3,5-dimethyl-piperazin-1-yl]-3-oxopropyl}-3,5-dimethyl-1H-pyrrol-2-ylmethylene}- 1,3-dihydro-indol-2-one 162

3-{4-{3-[trans-3,5-Dimethyl-piperazin-1-yl]-3-oxo-propyl}-3,5-dimethyl-1H- pyrrol-2-ylmethylene}-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one 163

4-(2-Fluoro-phenyl)-3-[1-[5-(2- pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 164

4-(3-Fluoro-phenyl)-3-[1-[5-(2- pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 165

4-(2-Fluoro-phenyl)-3-[1-[5-(2- morpholin-4-yl-ethyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 166

4-(3-Fluoro-phenyl)-3-[1-[5-(2- morpholin-4-yl-ethyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)- tlidene]-1,3-dihydro-indol-2-one 167

4-(2-Fluoro-phenyl)-3-[1-{5-[2-(4-methyl-piperazin-1-yl)-ethyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 168

4-(3-Fluoro-phenyl)-3-[1-{5-[2-(4-methyl-piperazin-1-yl)-ethyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 169

5-[4-(4-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- diethylamino-ethyl)-amide 170

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- diethylamino-ethyl)-amide 171

5-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acidmethyl-(1-methyl-piperidin-4-yl)-amide 172

5-Methoxy-3-[1-[3-methyl-4- (morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-phenyl-1,3- dihydro-indol-2-one 173

5-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-carboxylic acid (2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)-amide 174

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)- amide 175

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-[1,2,3]triazol-2-yl-propyl)- amide 176

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)- amide 177

4-(3-Fluoro-phenyl)-3-[1-{5-methyl-3-[2-(4-methyl-piperazin-1-yl)-2-oxo- ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 178

2-{2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-N-methyl-N-(1- methyl-piperidin-4-yl)-acetamide179

3-[1-{3-[2-((3R,5S)-3,5-Dimethyl- piperazin-1-yl)-2-oxo-ethyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one 180

4-(3-Fluoro-phenyl)-3-[1-[5-methyl-3- (2-morpholin-4-yl-oxo-ethyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 181

4-(3-Fluoro-phenyl)-3-[1-{5-methyl-3-]2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-1H-pyrrol-2-yl}-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one182

4-(3-Fluoro-phenyl)-3-[1-{5-methyl-3-]2-oxo-2-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 183

2-{2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-N-(2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)-acetamide 184

2-{2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-N-(2-pyrrolidin- 1-yl-ethyl)-acetamide 185

2-{2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-2-yl}-N-(3-pyrrolidin- 1-yl-propyl)-acetamide 186

N-(2,4-Dioxo-1,2,3,4-tetrahydro- pyrimidin-5-ylmethyl)-2-{2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-acetamide 187

4-(2-Fluoro-phenyl)-3-[1-{5-methyl-3-[2-(4-methyl-piperazin-1-yl)-2-oxo- ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 188

2-{2-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-N-methyl-N-(1- methyl-pyridin-4-yl)-acetamide 189

3-[1-{3-[2-((3R,5S)-3,5-Dimethyl- piperazin-1-yl)-2-oxo-ethyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one 190

4-(2-Fluoro-phenyl)-3-[1-[5-methyl-3- (2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 191

4-(2-Fluoro-phenyl)-3-[1-{5-methyl-3-[2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-1H-pyrrol-2-yl}-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one192

4-(4-Chloro-phenyl)-3-[1-{3,5- dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 193

4-(4-Chloro-phenyl)-3-[1-{4-[3- ((3R,5S)-3,5-dimethyl-piperazin-1-yl)-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro- indol-2-one 194

3-[1-{3,5-Dimethyl-4-[3-(4-methyl- piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-yl}-meth-(Z)ylidene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one 195

5-[4-[3-(2-Hydroxy-ethyl)-phenyl]-2- oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 196

5-[4-[3-(2-Hydroxy-ethyl)-phenyl]-2- oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide 197

2-[4-[3-(2-Hydroxy-ethyl)-phenyl]-2- oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3- carboxylic acid(2-[1,2,3]triazol-1-yl- ethyl)-amide 198

3-[1-[3,5-Dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]- meth-(Z)-ylidene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one 199

4-(2-Chloro-phenyl)-3-[1-[3,5-dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1- carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 200

4-(4-Chloro-phenyl)-3-[1-[3,5-dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1- carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 201

4-(3-Chloro-phenyl)-3-[1-[3,5-dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1- carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 202

3-[1-[3,5-Dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)- 1,3-dihydro-indol-2-one 203

3-[1-[5-Methyl-3-{4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]- meth-(Z)-ylidene]-4-phenyl-1,3-dihydro-indol-2-one 204

4-(4-Chloro-phenyl)-3-[1-[5-methyl-3- (4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 205

4-(3-Fluoro-phenyl)-3-[1-[5-methyl-3- (4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 206

3-[1-[5-Methyl-3-(morpholine-4- carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-phenyl-1,3-dihydro-indol-2- one 207

4-(2-Chloro-phenyl)-3-[1-[5-methyl-3-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol- 2-one 208

4-(4-Chloro-phenyl)-3-[1-[5-methyl-3-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol- 2-one 209

4-(3-Fluoro-phenyl)-3-[1-[5-methyl-3-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol- 2-one 210

2-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid(2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin- 4-ylmethyl)-amide 211

4-(3-Chloro-phenyl)-3-[1-[3-methyl-4- (4-pyrrolidin-1-yl-piperidine-1-carbonyl]-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 212

4-(3-Chloro-phenyl)-3-[1-]3-methyl-4-(2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 213

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- morpholin-4-yl-ethyl)-amide 214

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid [3-(2-methyl-piperidin-1-yl)-propyl]-amide 215

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- piperidin-1-yl-ethyl)-amide 216

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- pyridin-4-yl-ethyl)-amide 217

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- pyrrolidin-1-yl-ethyl)-amide 218

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide 219

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)- amide 220

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)- amide 221

3-[1-{3,5-Dimethyl-4-[2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one 222

3-[1-{3,5-Dimethyl-4-[2-oxo-2-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)- ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(2-fluoro-phenyl)-1,3- dihydro-indol-2-one 223

3-{5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrol-3-yl}-N-(2-morpholin-4-yl-ethyl)-acetamide 224

3-[1-{4-[2-((3R,5S)-3,5-Dimethyl- piperazin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)- ylidene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one 225

2-{5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrol-3-yl}-N-(2-piperidin-1-yl-ethyl)-acetamide 226

2-{5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-N-(2-pyridin- 4-yl-ethyl)-acetamide 227

2-{5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrol-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-acetamide 228

3-[1-{3,5-Dimethyl-4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(2-fluoro- phenyl)-1,3-dihydro-indol-2-one 229

3-[1-[3,5-Dimethyl-4-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(2-fluoro-phenyl)-1,3- dihydro-indol-2-one 230

N-(2-Diethylamino-ethyl)-2-{5-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H- pyrrol-3-yl}-acetamide 231

4-(2-Chloro-phenyl)-3-[1-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 232

2-[4-(2-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- pyrrolidin-1-yl-ethyl)-amide 233

2-[4-(2-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3- pyrrolidin-1-yl-propyl)-amide234

4-(2-Chloro-phenyl)-3-[1-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H- pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 235

4-(3-Methoxy-phenyl)-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol- 2-one 236

4-(3-Chloro-4-fluoro-phenyl)-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H- pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 237

3-[1-{3,5-Dimethyl-4-[2-oco-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one 238

2-{5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrol-3-yl}-N-(2-hydroxy-3-[1,2,3]triazol-2-yl-propyl(- acetamide 239

3-[1-[3,5-Dimethyl-4-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3- dihydro-indol-2-one 240

4-(3-Fluoro-phenyl)-3-[1-{4-[2-(4- hydroxy-piperidin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one241

2-{5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrol-3-yl}-N-(2-morpholin-4-yl-ethyl)-acetamide 242

N-(2-Diethylamino-ethyl)-2-{5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H- pyrrol-3-yl}-acetamide 243

2-{5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrol-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-acetamide 244

3-[1-{4-[2-((3R,5S)-3,5-Dimethyl- piperazin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)- ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one 245

2-{5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-N-(2-pyridin- 4-yl-ethyl)-acetamide 246

2-Fluoro-5-{3-[1-[5-methyl-3-(4- pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2- oxo-2,3-dihydro-1H-indol-4-yl}-benzonitrile 247

2-[4-(3-Cyano-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]- 5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-[1,2,3]triazol-2-yl- propyl)-amide 248

5-{3-[1-[3-((3R,5S)-3,5-Dimethyl- piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-2-fluoro- benzonitrile 249

3-[1-[3-(3-Dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-4-(4-fluoro-phenyl)-1,3- dihydro-indol-2-one 250

3-[1-[3-(3-Dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-4-(2-fluoro-phenyl)-1,3- dihydro-indol-2-one 251

4-(4-Chloro-phenyl)-3-[1-[3-(3- dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 252

4-(3-Chloro-phenyl)-3-[1-[3-(3- dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 253

4-(2-Chloro-phenyl)-3-[1-[3-(3- dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 254

4-Biphenyl-3-yl-3-[1-[3,5-dimethyl-4- (4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 255

5-[4-Biphenyl-3-yl-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl- 1H-pyrrole-3-carboxylic acid (2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)- amide 256

4-Biphenyl-3-yl-3-[1-[4-((3R,5S)-3,5-dimethyl-piperazine-1-carbonyl)-3,5- dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 257

4-(3-Fluoro-phenyl)-3-[1-[4-(4-hydroxy-piperidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 258

3-[1-[3,5-Dimethyl-4-(4-pyridin-2-yl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)- 1,3-dihydro-indol-2-one 259

5-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-piperidine-1-yl-ethyl)-amide260

5-[4-Biphenyl-2-yl-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl- 1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 261

2-[4-Biphenyl-2-yl-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H- pyrrole-3-carboxylic acid(3-pyrrolidin- 1-yl-propyl)-amide 262

2-[4-(4-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3- pyrrolidin-1-yl-propyl)-amide263

2-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3- pyrrolidin-1-yl-propyl)-amide264

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3- pyrrolidin-1-yl-propyl)-amide265

2-[4-(4-Bromo-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3- pyrrolidin-1-yl-propyl)-amide266

5-Methyl-2-[2-oxo-4-phenyl-1,2- dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (3-pyrrolidin- 1-yl-propyl)-amide 267

5-[4-(3,5-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide 268

2-[4-(3,5-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid(3- pyrrolidin-1-yl-propyl)-amide 269

4-(3,5-Difluoro-phenyl)-3-[1-[3,5- dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 270

4-(3,5-Difluoro-phenyl)-3-[1-[5-methyl-3-(4-pyrrolidin-1-yl-piperidine-1- carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 271

3-[1-{3,5-Dimethyl-4-[3-(4-methyl- piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro- indol-2-one 272

3-[1-{4-[3-((3R,5S)-3,5-Dimethyl- piperazin-1-yl)-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)- ylidene]-4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro-indol-2-one 273

4-[3-(2-Hydroxy-ethyl)-phenyl]-3-[1-[3- methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 274

3-[1-[4-((3R,5S)-3,5-Dimethyl- piperazine-1-carbonyl)-3-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro- indol-2-one 275

2-[4-[3-(2-Hydroxy-ethyl)-phenyl]-2- oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3- carboxylic acid(3-pyrrolidin-1-yl- propyl)-amide 276

3-[1-[3-((3R,5S)-3,5-Dimethyl- piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro- indol-2-one 277

(3-{3-[1-[3-Methyl-4-(morpholine-4- carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene[-2-oxo-2,3-dihydro-1H-indol-4- yl}-phenyl)-acetic acid 278

4-{3-[2-((3R,5S)-3,5-Dimethyl- piperazin-1-yl)-2-oxo-ethyl]-phenyl}-3-[1-[3-methyl-4-(morpholine-4- carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 279

N-(2-Dimethylamino-ethyl)-2-(3-{3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2- oxo-2,3-dihydro-1H-indol-4-yl}-phenyl)-acetamide 280

5-[4-(2-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-phenyl-1H-pyrrole-3-carboxylic acidmethyl-(1-methyl-piperidin-4-yl)-amide 281

5-[4-(2-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-phenyl-1H-pyrrole-3-carboxylic acid (2- diethylamino-ethyl)-amide 282

5-[4-(2-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-phenyl-1H-pyrrole-3-carboxylic acid (2- pyrrolidin-1-yl-ethyl)-amide 283

N,N-Dimethyl-2-(3-{3-[1-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-phenyl)- acetamide 284

2-(3-{3-[1-[3,5-Dimethyl-4-(4- pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2- oxo-2,3-dihydro-1H-indol-4-yl}-phenyl)-N,N-dimethyl-acetamide 285

5-[4-(3-Dimethylcarbonylmethyl- phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide 286

3-[1-[3,5-Dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro-indol-2-one 287

4-[3-(2-Diethylamino-ethyl)-phenyl]- 3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-nl ylidene]-1,3-dihydro-indol-2-one288

4-[3-(2-Dimethylamino-ethyl)-phenyl]- 3-[1-[4-(4-hydroxy-piperidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 289

3-{3-[1-[3-Methyl-4-(morpholine-4- carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4- yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide 290

3-{3-[1-[3-Methyl-4-(morpholine-4- carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4- yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide 291

N-(2-Dimethylamino-ethyl)-3-{3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-benzamide 292

N-(3-Dimethylamino-propyl)-3-{3-[1- [3-methyl-4-(morpholine-4-carbonyl)-1H-oyrrol-2-yl]-meth-(Z)-ylidene]-2- oxo-2,3-dihydro-1H-indol-4-yl}-benzamide 293

N-Methyl-3-{3-[1-[3-methyl-4- (morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3- dihydro-1H-indol-4-yl}-N-(1-methyl-piperidin-4-yl)-benzamide 294

2-{2-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-N-(2-pyrrolidin- 1-yl-ethyl)-acetamide 295

N-(2,4-Dioxo-1,2,3,4-tetrahydro- pyrimidin-5-ylmethyl)-2-{2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol- (3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-acetamide 296

5-[4-(3-Amino-1H-indazol-5-yl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide297

5-[4-(3-Amino-1H-indazol-5-yl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide 298

3-{3-[1-[3-Methyl-4-(morpholine-4- carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4- yl}-benzoic acid 299

5-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-oyrrole-3-carboxylic acid(2-hydroxy-3-pyrrolidin-1-yl-propyl)- amide 300

3-[1-[4-(3-Diethylamino-pyrrolidin-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)- 1,3-dihydro-indol-2-one 301

3-[1-[3-(3-Diethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)- 1,3-dihydro-indol-2-one 302

3-[1-{4-[2-(3-Diethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H- pyrrol-2-yl}-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one 303

3-[1-{3-[2-(3-Diethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(3-fluoro- phenyl)-1,3-dihydro-indol-2-one 304

5-[4-(2,4-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide 305

2-[4-(2,4-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid(3- pyrrolidin-1-yl-propyl)-amide 306

4-(2,4-Difluoro-phenyl)-3-[1-[3,5- dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 307

4-(2,4-Difluoro-phenyl)-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol- 2-one 308

4-(3-Chloro-phenyl)-3-[1-[4-((R)-3- hydroxy-pyrrolidin-1-carbonyl)-3-methyl-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 309

4-(3-Chloro-phenyl)-3-[1-[3-((R)-3- hydroxy-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 310

4-(2-Fluoro-phenyl)-3-[1-[4-((R)-3- hydroxy-pyrrolidine-1-carbonyl)-3-methyl-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 311

4-(3-Fluoro-phenyl)-3-[1-[4-((R)-3- hydroxy-pyrrolidin-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 312

4-(3-Fluoro-phenyl)-3-[1-{4-[2-((R)-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one313

4-(2,6-Difluoro-phenyl)-3-[1-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 314

4-(2,6-Difluoro-phenyl)-3-[1-[3,5- dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 315

4-(3-Chloro-phenyl)-3-[1-[5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H- pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 316

4-(3-Fluoro-phenyl)-3-[1-[5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H- pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 317

5-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide 318

2-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid(3- pyrrolidin-1-yl-propyl)-amide 319

4-(2,6-Difluoro-phenyl)-3-[1-[3,5- dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 320

2-[4-(2-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid [2-(4-acetyl-piperazin-1-yl)-ethyl]-amide 321

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid [2-(4-acetyl-piperazin-1-yl)-ethyl]-amide 322

5-[4-(2-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid [2-(4-acetyl-piperazin-1-yl)-ethyl]-amide 323

5-[4-(2-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- piperidin-1-yl-ethyl)-amide 324

2-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- piperidin-1-yl-ethyl)-amide 325

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2- piperidin-1-yl-ethyl)-amide 326

2-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)- amide 327

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)- amide 328

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)- amide 329

5-[4-(2-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)- amide 330

5-[4-(3-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-hydroxy-3-pyrrolidin-1-yl-propyl)- amide 331

4-(3-Chloro-phenyl)-3-[1-[4-((S)-3- hydroxy-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 332

4-(3-Chloro-phenyl)-3-[1-[4-((S)-3- hydroxy-pyrrolidine-1-carbonyl)-3-methyl-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 333

4-(3-Chloro-phenyl)-3-[1-[3-((S)-3- hydroxy-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 334

4-(2-Fluoro-phenyl)-3-[1-[4-((S)-3- hydroxy-pyrrolidine-1-carbonyl)-3-methyl-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 335

4-(3-Fluoro-phenyl)-3-[1-[4-((S)-3- hydroxy-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 336

4-(3-Fluoro-phenyl)-3-[1-{4-[2-((S)-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one337

4-(3-Fluoro-phenyl)-3-[1-[4-(4-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 338

3-[1-(3,5-Dimethyl-4-morpholin-4- ylmethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3- dihydro-indol-2-one 339

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4,5,6,7-tetrahydro-1H-indole-3- carboxylic acid 340

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4,5,6,7-tetrahydro-1H-indole-3- carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide 341

4-(3-Fluoro-phenyl)-3-[1-[3-(3-hydroxy- pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 342

4-(2-Fluoro-phenyl)-3-[1-[3-((S)-2-(4- hydroxy-piperidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-5-methyl-1H- pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 343

4-(2-Fluoro-phenyl)-3-[1-{3-[((S)-2-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)- pyrrolidine-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 344

4-(3-Fluoro-phenyl)-3-[1-{4-[(S)-2-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)- pyrrolidine-1-carbonyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 345

4-(3-Fluoro-phenyl)-3-[1-{3-[(S)-2-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)- pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 346

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid {2-[4-(2-hydroxy-acetyl)-piperazin-1-yl]- ethyl}-amide 347

4-(2,6-Difluoro-phenyl)-3-[1-[4-(3-piperidin-1-yl-propionyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepin-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 348

5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-(3-methanesulfonyl-propyl)-2-methyl-1H- pyrrole-3-carboxylic acid 349

5-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-(3-methanesulfonyl-propyl)-2-methyl-1H- pyrrole-3-carboxylic acid 350

4-(3-Fluoro-phenyl)-3-[1-[4-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3-(3-methanesulfonyl-propyl)-5-methyl-1H- pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 351

4-(3-Fluoro-phenyl)-3-[1-[3-(3- methanesulfonyl-propyl)-5-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H- pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 352

4-(4-Chloro-phenyl)-3-[1-[3-(3- methanesulfonyl-propyl)-5-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H- pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 353

3-[1-[3-((3R,5S)-3,5-Dimethyl- piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethoxy)-phenyl]-1,3-dihydro- indol-2-one 354

3-[1-[3,5-Dimethyl-4-(4-methyl- piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-[3-(2-hydroxy- ethoxy)phenyl]-1,3-dihydro-indol-2-one 355

4-[3-(2-Hydroxy-ethoxy)-phenyl]-3-[1-[3-methyl-4-(4-methyl-piperazine-1- carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 356

5-[4-[3-(2-Hydroxy-ethoxy)-phenyl]-2- oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 357

3-[1-[3,5-Dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-[3-(2-hydroxy- ethoxy)-phenyl]-1,3-dihydro-indol-2-one 358

4-[3-(2-Hydroxy-ethoxy)-phenyl]-3-[1- [5-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 359

4-[3-(2-Hydroxy-ethoxy)-phenyl]-3-[1- [4-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 360

5-[4-(4-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 361

2-[4-(4-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid 362

3-[1-[3,5-Dimethyl-4-(4-morpholin-4-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro- phenyl)-1,3-dihydro-indol-2-one 363

4-(3,4-Dimethoxy-phenyl)-3-[1-[3- methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 364

4-(3,4-Dimethoxy-phenyl)-3-[1-[3- ((3R,5S)-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 365

5-[4-(3,4-Dimethoxy-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide 366

2-[4-(3,4-Dimethoxy-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid(3- pyrrolidin-1-yl-propyl)-amide 367

4-(3,4-Dimethoxy-phenyl)-3-[1-[5-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one368

4-(3,4-Dimethoxy-phenyl)-3-[1-[4-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 369

2,4-Dimethyl-5-[4-(3-methylcarbamoyl-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide 370

5-[4-(4-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid[2-(1,1-dioxo-1□-thiomorpholin-4-yl)- ethyl]-amide 371

5-[4-(2-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid [2-(1,1-dioxo-1□-thiomorpholin-4-yl)- ethyl]-amide 372

5-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4- methyl-1H-pyrrole-3-carboxylic acid[2- (1,1-dioxo-1□-thiomorpholin-4-yl)- ethyl]-amide 373

5-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl[-2,4- dimethyl-1H-pyrrole-3-carboxylicacid [2-(1,1-dioxo-1□-thiomorpholin-4-yl)- ethyl]-amide 374

2-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid[2- (1,1-dioxo-1□-thiomorpholin-4-yl)- ethyl]-amide 375

5-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylicacid 376

2-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid377

5-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4- methyl-1H-pyrrole-3-carboxylic acid378

3-[1-(4-{(S)-2-[(Cyclopropylmethyl- amino)-methyl]-pyrrolidine-1-carbonyl}-3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)- 1,3-dihydro-indol-2-one 379

3-[1-(3-{(S)-2-[(Cyclopropylmethyl- amino)-methyl]-pyrrolidine-1-carbonyl}-5-methyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)- 1,3-dihydro-indol-2-one 380

4-(2,6-Difluoro-phenyl)-3-[1-[4-((S)-pyrrolidine-2-carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepin-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 381

2-[4-(3,5-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid(2- hydroxy-3-pyrrolidin-1-yl-propyl)- amide 382

2-[4-(2,4-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid(2- hydroxy-3-pyrrolidin-1-yl-propyl)- amide 383

2-[4-(3-Chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]- 5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)- amide 384

2-[4-(4-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidine-1-yl-propyl)- amide 385

2-[4-(3,5-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid(2- hydroxy-3-pyrrolidin-1-yl-propyl)- methyl-amide 386

4-(3-Fluoro-phenyl)-3-[1-[4-((R)-3- hydroxy-pyrrolin-1-ylmethyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 387

4-(2-Fluoro-phenyl)-3-[1-[4-(3-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 388

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl-]-5-methyl-1H-pyrrole-3-carboxylic acid (2- piperidin-1-yl-ethyl)-amide 389

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid [2-(3-acetylamino-pyrrolidin-1-yl)-ethyl]- amide 390

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide 391

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid [2-(4-hydroxy-piperidine-1-yl)-ethyl]-amide 392

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid [3-(1,1-dioxo-1□-thiomorpholin-4-yl)-2- hydroxy-propyl]-amide 393

5-[4-(4-Chloro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid[3-(1,1-dioxo-1□-thiomorpholin-4-yl)- 2-hydroxy-propyl]-amide 394

5-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4- methyl-1H-pyrrole-3-carboxylic acid[3- (1,1-dioxo-1□-thiomorpholin-4-yl)-2- hydroxy-propyl]-amide 395

4-(2,6-Difluoro-phenyl)-3-[1-[3-methyl- 4-((S)-3-pyrrolidin-1-ylmethyl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 396

4-(4-Chloro-phenyl)-3-[1-[3,5-dimethyl- 4-((S)-3-pyrrolidin-1-ylmethyl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 397

4-(3-Fluoro-phenyl)-3-[1-[5-methyl-3-(4-pyrrolidin-1-ylmethyl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 398

3-[1-[3,5-Dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrol-2- yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one 399

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid [2-(2,2,2-trifluoro-ethylamino)-ethyl]- amide 400

3-[1-[4-(1-Acetyl-piperidine-4- carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepin-2-yl]-meth-(Z)- ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one 401

(R)-1-{2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]- 5-methyl-1H-pyrrole-3-carbonyl}-piperidine-3-carboxylic acid cyclopropylamide 402

4-(3-Fluoro-phenyl)-3-[1-[4-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H- pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 403

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (3- pyrrolidin-1-yl-propyl)-amide404

3-[1-[3,5-Dimethyl-4-(1-methyl- piperidin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3- dihydro-indol-2-one 405

3-[1-[3,5-Dimethyl-4-(1-methyl- piperidin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(4-fluoro-phenyl)-1,3- dihydro-indol-2-one 406

4-(2,3-Difluoro-phenyl)-3-[1-[3,5- dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 407

4-(3,5-Difluoro-phenyl)-3-[1-[3,5- dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 408

4-(2,6-Dimethyl-phenyl)-3-[1-[3,5- dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 409

4-(3,4-Dimethoxy-phenyl)-3-[1-[3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 410

2-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid411

5-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylicacid 412

4-(2,4-Difluoro-phenyl)-3-[1-[3,5-dimethyl-04-(1-methyl-piperidin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 413

4-(2,3-Difluoro-phenyl)-3-[1-[3,5- dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 414

4-(2,3-Difluoro-phenyl)-3-[1-[3,5- dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 415

4-(2,3-Difluoro-phenyl)-3-[1-[3,5- dimethyl-4-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H- pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 416

4-(2,3-Difluoro-phenyl)-3-[1-[3- ((3R,5S)-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 417

2-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid(3- pyrrolidin-1-yl-propyl)-amide 418

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-iodo-4-methyl-1H-pyrrole-3-carboxylic acid(3-pyrrolidin-1-yl-propyl)-amide 419

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid[(S)-2-hydroxy-3-(3-methyl-2,5-dioxo- imidazolin-1-yl)-propyl]-amide 420

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid[(R)-2-hydroxy-3-(3-methyl-2,5-dioxo- imidazolin-1-yl)-propyl]-amide 421

4-(3-Fluoro-phenyl)-3-[1-[5-methyl-3- (3-morpholin-4-yl-azetidine-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one 422

3-[1-{3-[3-((2R,6S)-2,6-Dimethyl- morpholin-4-yl)-azetidine-1-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)- ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one 423

4-(3-Fluoro-phenyl)-3-[1-{3-[(S)-2-((S)-3-fluoro-pyrrolidin-1-ylmethyl)- pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 424

4-(3-Fluoro-phenyl)-3-[1-{3-[(R)-2-((S)-3-fluoro-pyrrolidin-1-ylmethyl)- pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3- dihydro-indol-2-one 425

3-[1-[3-(4-Cyclopropylamino- piperidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene[-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one 426

3-[1-[3-((2R,4R)-2- Cyclopropylaminomethyl-4-hydroxy-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one 427

2-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid(3- cyclopropylamino-2-hydroxy-propyl)- amide 428

2-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5- methyl-1H-pyrrole-3-carboxylic acid(2- hydroxy-3-pyrrolidin-1-yl-propyl)- amide 429

4-(2,3-Difluoro-phenyl)-3-[1-{3-[(S)-2-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-5-methyl-1H- pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 430

4-(2,3-Difluoro-phenyl)-3-[1-{3-[(S)-2-((S)-3-fluoro-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-5-methyl-1H- pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one 431

3-[1-[3-((S)-3- Cyclopropylaminomethyl-piperidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)- 1,3-dihydro-indol-2-one 432

4-(4-Chloro-phenyl)-3-[1-[3-((S)-3- cyclopropylaminomethyl-piperidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2- one 433

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)- methyl-amide 434

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2- dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3-cyclopropylamino-2-hydroxy-propyl)- amide 435

4-(3-Fluoro-phenyl)-3-[1-[4-(2- pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)- ylidene]-1,3-dihydro-indol-2-one

[0078] In a second aspect, this inventions is directed to apharmaceutical composition comprising one or more compounds of formula(I) or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.

[0079] Biochemistry

[0080] Another aspect of this invention relates to a method for themodulation of the catalytic activity of a PK by contacting a PK with acompound of this invention or a physiologically acceptable salt thereof.

[0081] A further aspect of this invention is that the modulation of thecatalytic activity of PKs using a compound of this invention may becarried out in vitro or in vivo.

[0082] A still further aspect of this invention is that the proteinkinase whose catalytic activity is being modulated by a compound of thisinvention is selected from the group consisting of receptor proteintyrosine kinases, cellular tyrosine kinases and serine-threoninekinases.

[0083] It is an aspect of this invention that the receptor tyrosineprotein kinase whose catalytic activity is modulated by a compound ofthis invention is selected from the group consisting of EGF, HER2, HER3,HER4, IR, IGF-1R, IRR, PDGFRα, PDGFRβ, CSFIR, C-Kit, C-fms, Flk-1R,Flk4, KDR/Flk-1, Flt1, FGFR-1R, FGFR-2R, FGFR-3R, FGFR-4R, MET, DDR-1and DDR-2.

[0084] In addition, it is an aspect of this invention that the cellulartyrosine kinase whose catalytic activity is modulated by a compound ofthis invention is selected from the group consisting of Src, Frk, Btk,Csk, Abl, ZAP70, Fes/Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck,Fgr and Yrk.

[0085] Another aspect of this invention is that the serine-threonineprotein kinase whose catalytic activity is modulated by a compound ofthis invention is selected from the group consisting of CDK2, Raf, NEKand BUB1.

[0086] Another aspect of this inventions relates to a method fortreating or preventing a protein kinase related disorder in an organismcomprising administering a therapeutically effective amount of acompound or a salt thereof Formula 1 to an organism.

[0087] It is an aspect of this invention that the above-referencedprotein kinase related disorder is selected from the group consisting ofa receptor protein tyrosine kinase related disorder, a cellular tyrosinekinase disorder and a serine-threonine kinase related disorder.

[0088] In yet another aspect of this invention, the above referencedprotein kinase related disorder is selected from the group consisting ofa Met related disorder, a PDGFR related disorder, an IGFR relateddisorder and a flk related disorder.

[0089] The above referenced protein kinase related disorders include byway of example and not limitation, cancers such as lung cancer, NSCLC(non small cell ling cancer), bone cancer, pancreatic cancer, skincancer, cancer of the head and neck, cutaneous or intraocular melanoma,uterine cancer, ovarian cancer, rectal cancer, cancer of the analregion, stomach cancer, colon cancer, breast cancer, gynecologic tumors(e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma ofthe endometrium, carcinoma of the cervix, carcinoma of the vagina orcarcinoma of the vulva), Hodgkin's Disease, cancer of the esophagus,cancer of the small intestine, cancer of the endocrine system (e.g.,cancer of the thyroid, parathyroid or adrenal glands), sarcomas of softtissues, cancer of the urethra, cancer of the penis, prostate cancer,chronic or acute leukemia, solid tumors of childhood, lynphocyticlymphomas, cancer of the bladder, cancer of the kidney or uerter (e.g.,renal cell carcinoma, carcinoma of the renal pelvis), pediatricmalignancy, neoplasms of the cnetral nervous system (e.g., primary CNSlymphoma, spinal axis tumors, brain stem glioma or pituitary adenomas),Barrett's esophagus (pre-malignant syndrome), neoplastic cutaneousdisease, psoriasis, mycoses fungoides and benign prostatic hypertrophy,diabetes related diseases such as diabetic retinopathy, retinal ischemiaand retinal neovascularization, hepatic cirrhosis, cardiovasculardisease such as atherosclerosis, immunological disease such asautoimmune disease and renal disease. Preferably, the disease is cancersuch as acute myeloid leukemia and colorectal cancer.

[0090] The above referenced protein kinase related disorder alsoincludes disorders selected from the group consisting of diabetes, ahyper-proliferation disorder, hyperproliferative disorders of thekidney, von Hippel-Lindau disease, restenosis, fibrosis, psoriasis,osteoarthritis, rheumatoid arthritis, an inflammatory disorder andangiogenesis in yet another aspect of this invention.

[0091] Additional disorders which may be treated or prevented using thecompounds of this invention are immunological disorders such asautoimmune diseases (e.g., AIDS, lupus, etc.) and cardiovasculardisorders such as atherosclerosis.

[0092] It is an aspect of this invention that the protein kinase relateddisorder being treated or prevented by administration of a compound ofthis invention is a CDK2 related disorder.

[0093] The organism in which the protein kinase related disorder isbeing treated or prevented is a human being in yet another aspect ofthis invention.

[0094] It is as aspect of this invention that a chemical compound thatmodulates the catalytic activity of a protein kinase may be identifiedby contacting cells expressing said protein kinase with a compound or asalt thereof of Formula 1 and then monitoring said cells for an effect.

[0095] The above-referenced effect is selected from a change or anabsence of change in a cell phenotype, a change or absence of change inthe catalytic activity of said protein kinase or a change or absence ofchange in the interaction of said protein kinase with a natural bindingpartner in a final aspect of this invention.

[0096] It is also an aspect of this invention that a compound describedherein, or its salt, might be combined with other chemotherapeuticagents for the treatment of the diseases and disorders discussed above.For instance, a compound or salt of this invention might be combinedwith alkylating agents such as fluorouracil (5-FU) alone or in furthercombination with leukovorin; or other alkylating agents such as, withoutlimitation, other pyrimidine analogs such as UFT, capecitabine,gemcitabine and cytarabine, the alkyl sulfonates, e.g., busulfan (usedin the treatment of chronic granulocytic leukemia), improsulfan andpiposulfan; aziridines, e.g., benzodepa, carboquone, meturedepa anduredepa; ethyleneimines and methylmelamines, e.g., altretamine,triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylolmelamine; and the nitrogenmustards, e.g., chlorambucil (used in the treatment of chroniclymphocytic leukemia, primary macroglobulinemia and non-Hodgkin'slymphoma), cyclophosphamide (used in the treatment of Hodgkin's disease,multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lungcancer, Wilm's tumor and rhabdomyosarcoma), estramustine, ifosfamide,novembrichin, prednimustine and uracil mustard (used in the treatment ofprimary thrombocytosis, non-Hodgkin's lymphoma, Hodgkin's disease andovarian cancer); and triazines, e.g., dacarbazine (used in the treatmentof soft tissue sarcoma).

[0097] Likewise a compound or salt of this invention might be expectedto have a beneficial effect in combination with other antimetabolitechemotherapeutic agents such as, without limitation, folic acid analogs,e.g. methotrexate (used in the treatment of acute lymphocytic leukemia,choriocarcinoma, mycosis fungiodes breast cancer, head and neck cancerand osteogenic sarcoma) and pteropterin; and the purine analogs such asmercaptopurine and thioguanine which find use in the treatment of acutegranulocytic, acute lymphocytic and chronic granulocytic leukemias.

[0098] A compound or salt of this invention might also be expected toprove efficacious in combination with natural product basedchemotherapeutic agents such as, without limitation, the vincaalkaloids, e.g., vinblastin (used in the treatment of breast andtesticular cancer), vincristine and vindesine; the epipodophylotoxins,e.g., etoposide and teniposide, both of which are useful in thetreatment of testicular cancer and Kaposi's sarcoma; the antibioticchemotherapeutic agents, e.g., daunorubicin, doxorubicin, epirubicin,mitomycin (used to treat stomach, cervix, colon, breast, bladder andpancreatic cancer), dactinomycin, temozolomide, plicamycin, bleomycin(used in the treatment of skin, esophagus and genitourinary tractcancer); and the enzymatic chemotherapeutic agents such asL-asparaginase.

[0099] In addition to the above, a compound or salt of this inventionmight be expected to have a beneficial effect used in combination withthe platinum coordination complexes (cisplatin, etc.); substituted ureassuch as hydroxyurea; methylhydrazine derivatives, e.g., procarbazine;adrenocortical suppressants, e.g., mitotane, aminoglutethimide; andhormone and hormone antagonists such as the adrenocorticosteriods (e.g.,prednisone), progestins (e.g., hydroxyprogesterone caproate); estrogens(e.g., diethylstilbesterol); antiestrogens such as tamoxifen; androgens,e.g., testosterone propionate; and aromatase inhibitors (such asanastrozole.

[0100] Finally, the combination of a compound of this invention might beexpected to be particularly effective in combination with mitoxantroneor paclitaxel for the treatment of solid tumor cancers or leukemias suchas, without limitation, acute myelogenous (non-lymphocytic) leukemia.

[0101] The above method can be carried out in combination with achemotherapeutic agent selected from the gorup consisting of mitoticinhibitors, alkylating agetns, antimetabolites, cell cycle inhibitors,enzymes, topoisomerase inhibitors, biological response modifiers,anti-hormones, antiangiogenic agents such as MMP-2, MMP-9 and COX-2inhibitors, and anti-androgens.

[0102] Examples of useful COX-II inhibitors include Vioxx™, CELEBREX™(alecoxib), valdecoxib, paracoxib, rofecoxib, and Cox 189. Examples ofuseful matrix metalloproteinase inhibitors are described in WO 96/33172(published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996),European Patent Application No. 97304971.1 (filed Jul. 8, 1997),European Patent Application No. 99308617.2 (filed Oct. 29, 1999), WO98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29,1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915 (publishedAug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO 98/30566(published Jul. 16, 1998), European Patent Publication 606,046(published Jul. 13, 1994), European Patent Publication 931,788(published Jul. 28, 1999), WO 90/05719 (published May 31, 1990), WO99/52910 (published Oct. 21, 1999), WO 99/52889 (published Oct. 21,1999), WO 99/29667 (published Jun. 17, 1999), PCT InternationalApplication No. PCT/IB98/01113 (filed Jul. 21, 1998), European PatentApplication No. 99302232.1 (filed Mar. 25, 1999), Great Britain patentapplication number 9912961.1 (filed Jun. 3, 1999), U.S. provisionalapplication Ser. No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. No.5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued Jan.19, 1999), and European Patent Publication 780,386 (published Jun. 25,1997), all of which are incorporated herein in their entireties byreference. Preferred MMP-2 and MMP-9 inhibitors are those that havelittle or no activity inhibiting MMP-1. More preferred, are those thatselectively inhibit MMP-2 and/or MMP-9 relative to the othermatrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-I 1, MMP-12, and MMP-13).

[0103] Some specific examples of MMP inhibitors useful in the presentinvention are AG-3340, RO 32-3555, RS 13-0830, and the compounds recitedin the following list:

[0104]3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionic acid;3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.I]octane-3-carboxylic acid hydroxyamide; (2R, 3R)1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide;3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic acid;4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide; (R)3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylicacid hydroxyamide; (2R, 3R)1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;3-[[(4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionicacid;3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionicacid;3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide;3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; and (R)3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid hydroxyamide; and pharmaceutically acceptable salts and solvatesof said compounds.

[0105] Other anti-angiogenesis agents, including other COX-II inhibitorsand other MMP inhibitors, can also be used in the present invention.

[0106] A compound of Formula (I) can also be used with signaltransduction inhibitors, such as agents that can inhibit EGFR (epidermalgrowth factor receptor) responses, such as EGFR antibodies, EGFantibodies, and molecules that are EGFR inhibitors; VEGF (vascularendothelial growth factor) inhibitors; and erbB2 receptor inhibitors,such as organic molecules or antibodies that bind to the erbB2 receptor,for example, HERCEPTIN™ (Genentech, Inc. of South San Francisco, Calif.,USA). EGFR inhibitors are described in, for example in WO 95/19970(published Jul. 27, 1995), WO 98/14451 (published Apr. 9, 1998), WO98/02434 (published Jan. 22, 1998), and U.S. Pat. No. 5,747,498 (issuedMay 5, 1998), and such substances can be used in the present inventionas described herein.

[0107] EGFR-inhibiting agents include, but are not limited to, themonoclonal antibodies C225 and anti-EGFR 22Mab (ImClone SystemsIncorporated of New York, N.Y., USA), the compounds ZD-1839(AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc.of Annandale, N.J., USA), and OLX-103 (Merck & Co. of WhitehouseStation, N.J., USA), VRCTC-310 (Ventech Research) and EGF fusion toxin(Seragen Inc. of Hopkinton, Mass.).

[0108] These and other EGFR-inhibiting agents can be used in the presentinvention.

[0109] VEGF inhibitors, for example SU-5416, SU 11248, SU-6668 (SugenInc. of South San Francisco, Calif., USA), can also be combined with acompound of Formula (I). VEGF inhibitors are described in, for examplein WO 99/24440 (published May 20, 1999), PCT International ApplicationPCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug.17,1995), WO 99/61422 (published Dec. 2,1999), U.S. Pat. No. 5,834,504(issued Nov. 10, 1998), WO 01/60814,WO 98/50356 (published Nov. 12,1998), U.S. Pat. No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No.5,886,020 (issued Mar. 23, 1999), U.S. Pat. No. 5,792,783 (issued Aug.11, 1998), WO 99/10349 (published Mar. 4, 1999), WO 97/32856 (publishedSep. 12, 1997), WO 97/22596 (published Jun.26, 1997), WO 98/54093(published Dec. 3, 1998), WO 98/02438 (published Jan. 22, 1998), WO99/16755 (published Apr. 8, 1999), and WO 98/02437 (published Jan. 22,1998), all of which are incorporated herein in their entireties byreference. Other examples of some specific VEGF inhibitors useful in thepresent invention are IM862 (Cytran Inc. of Kirkland, Wash., USA);anti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco,Calif.; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder,Colo.) and Chiron (Emeryville, Calif.). These and other VEGF inhibitorscan be used in the present invention as described herein.

[0110] ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcomeplc), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc.of TheWoodlands, Tex., USA) and 2B- I (Chiron), can furthermore becombined with a compound of Formula (I) for example those indicated inWO 98/02434 (published Jan. 22, 1998), WO 99/35146 (published Jul. 15,1999), WO 99/35132 (published Jul. 15, 1999), WO 98/02437 (publishedJan. 22, 1998), WO 97/13760 (published Apr. 17, 1997), WO 95/19970(published Jul. 27, 1995), U.S. Pat. No. 5,587,458 (issued Dec. 24,1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2, 1999), which are allhereby incorporated herein in their entireties by reference. ErbB2receptor inhibitors useful in the present invention are also describedin U.S. provisional application No. 60/117,341, filed Jan. 27, 1999, andin U.S. provisional application No. 60/117,346, filed Jan. 27,1999, bothof which are incorporated in their entireties herein by reference. TheerbB2 receptor inhibitor compounds and substance described in theaforementioned PCT applications, U.S. patents, and U.S. provisionalapplications, as well as other compounds and substances that inhibit theerbB2 receptor, can be used with a compound of Formula (I), inaccordance with the present invention.

[0111] A compound of Formula (I) can also be used with other agentsuseful in treating cancer, including, but not limited to, agents capableof enhancing antitumor immune responses, such as CTLA4 (cytotoxiclymphocite antigen 4) antibodies, and other agents capable of blockingCTLA4; and anti-proliferative agents such as other farnesyl proteintransferase inhibitors, for example the farnesyl protein transferaseinhibitors described in the references cited in the “Background”section, of U.S. Pat. No, 6,258,824 Bl. Specific CTLA4 antibodies thatcan be used in the present invention include those described in U.S.provisional application No. 60/113,647 (filed Dec. 23, 1998) which isincorporated by reference in its entirety, however other CTLA4antibodies can be used in the present invention.

[0112] The above method can be also be carried out in combination withradiation therapy, wherein the amount of a compound of Formula (I) incombination with the radiation therapy effective in treating the abovediseases.

[0113] Techniques for administering radiation therapy are known in theart, and these techniques can be used in the combination therapydescribed herein. The administration of the compound of the invention inthis combination therapy can be determined as described herein.

[0114] Another aspect of the invention is directed ot the use of acompound of Formula (I) in the preparation of a medicament, which isuseful in the treatment of a disease mediated by abnormal Met kinaseactivity.

DETAILED DESCRIPTION OF THE INVENTION

[0115] I. Definitions

[0116] The terms “indolinone”, “2-indolinone” and “indolin-2-one” areused interchangeably herein to refer to a molecule having the chemicalstructure:

[0117] “Pyrrole” refers to a molecule having the chemical structure:

[0118] “Pyrrole-substituted 2-indolinone” and“3-pyrrolidinyl-2-indolinone” are used interchangeably herein to referto a chemical compound having the general structure shown in Formula I.

[0119] “Pharmaceutically acceptable salt” or “pharmaceuticallyacceptable salt thereof” refer to those salts which retain thebiological effectiveness and properties of the free bases and which areobtained by reaction with inorganic or organic acids, such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, acetic acid, benzenesulfonicacid (besylate), benzoic acid, camphorsulfonic acid, citric acid,fumaric acid, gluconic acid, glutamic acid, isethionic acid, lacticacid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid,pantothenic acid, succinic acid, tartaric acid, and the like.

[0120] A “pharmaceutical composition” refers to a mixture of one or moreof the compounds described herein, or physiologically acceptable saltsthereof, with other chemical components, such as physiologicallyacceptable carriers and excipients. The purpose of a pharmaceuticalcomposition is to facilitate administration of a compound to anorganism.

[0121] As used herein, a “physiologically acceptable carrier” refers toa carrier or diluent that does not cause significant irritation to anorganism and does not abrogate the biological activity and properties ofthe administered compound.

[0122] An “excipient” refers to an inert substance added to apharmaceutical composition to further facilitate administration of acompound. Examples, without limitation, of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives (including microcrystalline cellulose), gelatin,vegetable oils, polyethylene glycols, diluents, granulating agents,lubricants, binders, disintegrating agents, and the like.

[0123] “Alkyl” refers to a saturated aliphatic hydrocarbon includingstraight chain, branched chain or cyclic groups. Preferably, the alkylgroup has 1 to 20 carbon atoms (whenever a numerical range; e.g.,“1-20”, is stated herein, it means that the group, in this case thealkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms,etc. up to and including 20 carbon atoms). More preferably, it is amedium size alkyl having 1 to 10 carbon atoms. Most preferably, it is alower alkyl having I to 4 carbon atoms. The alkyl group may besubstituted or unsubstituted. When substituted, the substituent group(s)is preferably one or more individually selected from halogen, —OR⁶,—COR⁶, —COOR⁶, OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷, —CN, —NO₂, —CX₃, —SR⁶,—SOR⁶, —SO₂R⁶, —SO₂OR⁶, —SO₂NR⁶R⁷, thiocarbonyl, —R⁶NSO₂R⁷,perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,heterocycle, heteroaryl and aryl.

[0124] “Alkenyl” refers to an aliphatic hydrocarbon having at least onecarbon-carbon double bond, including straight chain, branched chain orcyclic groups having at least one carbon-carbon double bond. Preferably,the alkenyl group has 2 to 20 carbon atoms (whenever a numerical range;e.g., “2-20”, is stated herein, it means that the group, in this casethe alkenyl group, may contain 2 carbon atoms, 3 carbon atoms, etc. upto and including 20 carbon atoms). More preferably, it is a medium sizealkenyl having 2 to 10 carbon atoms. Most preferably, it is a loweralkenyl having 2 to 6 carbon atoms. The alkenyl group may be substitutedor unsubstituted. When substituted, the substituent group(s) ispreferably one or more individually selected from halogen, —OR⁶, —COR⁶,—COOR⁶, OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷,—CN, —NO₂, —CX₃, —SR⁶, —SO₂R⁶,—SO₂R⁶, —SO₂OR⁶, —SO₂NR⁶R⁷, thiocarbonyl, —R⁶NSO₂R⁷, perfluoroalkyl,O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium,lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycle,heteroaryl and aryl.

[0125] “Alkynyl” refers to an aliphatic hydrocarbon having at least onecarbon-carbon triple bond, including straight chain, branched chain orcyclic groups having at least one carbon-carbon triple bond. Preferably,the alkenyl group has 2 to 20 carbon atoms (whenever a numerical range;e.g., “2-20”, is stated herein, it means that the group, in this casethe alkynyl group, may contain 2 carbon atoms, 3 carbon atoms, etc. upto and including 20 carbon atoms). More preferably, it is a medium sizealkynyl having 2 to 10 carbon atoms. Most preferably, it is a loweralkynyl having 2 to 6 carbon atoms. The alkynyl group may be substitutedor unsubstituted. When substituted, the substituent group(s) ispreferably one or more individually selected from halogen, —OR⁶, —COR⁶,—COOR⁶, OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷ , —NR⁶R⁷ , —CN, —NO₂, —CX₃, —SR⁶,—SOR⁶, —SO₂R⁶, —SO₂ NR⁶R⁷, thiocarbonyl, —R⁶NSO₂R⁷, perfluoroalkyl,O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium,lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycle,heteroaryl and aryl.

[0126] A “cycloalkyl” group refers to an all-carbon monocyclic or fusedring (i.e., rings which share an adjacent pair of carbon atoms) groupwherein one of more of the rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,adamantane, cyclohexadiene, cycloheptane and, cycloheptatriene. Acycloalkyl group may be substituted or unsubstituted. When substituted,the substituent group(s) is preferably one or more individually selectedfrom halogen, —OR⁶, —COR⁶, —COOR⁶, OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷ , —NR⁶R⁷ ,—CN, —NO₂, —CX₃, —SR⁶, —SOR⁶, —SO₂R⁶, —SO₂ NR⁶R⁷, thiocarbonyl,—R⁶NSO₂R⁷, perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocycle, heteroaryl and aryl.

[0127] An “aryl” group refers to an all-carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, naphthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted, the substituted group(s) is preferably one or more selectedhalogen, —OR⁶, —COR⁶, —COOR⁶, OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷ , —NR⁶R⁷ , —CN,—NO₂, —CX₃, —SR⁶, —SOR⁶, —SO₂R⁶, —SO₂ NR⁶R⁷, thiocarbonyl, —R⁶NSO₂R⁷,perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,heterocycle, heteroaryl and aryl.

[0128] As used herein, a “heteroaryl” group refers to a monocyclic orfused ring (i.e., rings which share an adjacent pair of atoms) grouphaving in the ring(s) one or more atoms selected from the groupconsisting of nitrogen, oxygen and sulfur and, in addition, having acompletely conjugated pi-electron system. Examples, without limitation,of heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole,thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline,purine and carbazole. The heteroaryl group may be substituted orunsubstituted. When substituted, the substituted group(s) is preferablyone or more selected from halogen, —OR⁶, —COR⁶, —COOR⁶, OCOR⁶, —CONR⁶R⁷,—R⁶NCOR⁷, —NR⁶R⁷, —CN, —NO₂, —CX₃, —SR⁶, —SOR⁶, —SO₂R⁶, —SO₂R⁶,—SO₂NR⁶R⁷, thiocarbonyl, —R⁶NSO₂R⁷, perfluoroalkyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycle, heteroaryland aryl, where X is halogen.

[0129] A “heterocyclic ring” or “heterocycle” group refers to amonocyclic or fused ring group having in the ring(s) one or more atomsselected from the group consisting of nitrogen, oxygen and sulfur. Therings may also have one or more double bonds. However, the rings may ormay not have a completely conjugated pi-electron system. Theheterocyclic ring may be substituted or unsubstituted. The heterocyciring may contain one or more oxo groups. When substituted, thesubstituted group(s) is preferably one or more selected halogen, —OR⁶,—COR⁶, —COOR⁶, OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷, —CN, —NO₂, —CX₃, —SR⁶,—SOR⁶, —SO₂R⁶, —SO₂OR⁶, —SO₂NR⁶R⁷, thiocarbonyl, —R⁶NSO₂R⁷,perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,silyl, ammonium, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,heterocycle, heteroaryl and aryl.

[0130] X refers to a halogen group selected from the group consisting offluorine, chlorine, bromine and iodine.

[0131] The definitions of R¹-R¹³ are defined in the presentspecification.

[0132] Compounds that have the same molecular formula but difer in thenature or sequence of bonding of their atoms or arrangements of theiratoms in space are termed isomers. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

[0133] The compounds of this invention may possess one or moreasymmetric centers; such compounds can therefore be produced asindividual (R)- or (S)-stereoisomers or as mixtures thereof. Forexample, if the R⁶ substituent in a compound of formula (I) is2-hydroxyethyl, then the carbon to which the hydroxy group is attachedis an asymmetric center and therefore the compound of Formula (I) canexist as an (R)- or (S)-stereoisomer. Unless indicated otherwise, thedescription or naming of a particular compound in the specification andclaims is intended to include both individual enantiomers and mixtures,racemic or otherwise, thereof. The methods for the determination ofstereochemistry and the separation of stereoisomers are well-known inthe art (see discussion in Chapter 4 of “Advanced Organic Chemistry”,4th edition J. March, John Wiley and Sons, New York, 1992).

[0134] The compounds of Formula (I) may exhibit the phenomena oftautomerism and structural isomerism. For example, the compoundsdescribed herein may adopt an E or a Z configuration about the doublebond connecting the 2-indolinone moiety to the pyrrole moiety or theymay be a mixture of E and Z. This invention encompasses any tautomericor structural isomeric form and mixtures thereof which possess theability to modulate RTK, CTK and/or STK activity and is not limited toany one tautomeric or structural isomeric form.

[0135] It is contemplated that a compound of Formula (I) would bemetabolized by enzymes in the body of the organism such as human beingto generate a metabolite that can modulate the activity of the proteinkinases. Such metabolites are within the scope of the present invention.

[0136] As used herein, “PK” refers to receptor protein tyrosine kinase(RTKs), non-receptor or “cellular” tyrosine kinase (CTKs) andserine-threonine kinases (STKs).

[0137] The term “method” refers to manners, means, techniques andprocedures for accomplishing a given task including, but not limited to,those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby, practitioners of the chemical, pharmaceutical, biological,biochemical and medical arts.

[0138] As used herein, the term “modulation” or “modulating” refers tothe alteration of the catalytic activity of RTKs, CTKs and STKs. Inparticular, modulating refers to the activation of the catalyticactivity of RTKs, CTKs and STKs, preferably the activation or inhibitionof the catalytic activity of RTKs, CTKs and STKs, depending on theconcentration of the compound or salt to which the RTK, CTK or STK isexposed or, more preferably, the inhibition of the catalytic activity ofRTKs, CTKs and STKs.

[0139] The term “catalytic activity” as used herein refers to the rateof phosphorylation of tyrosine under the influence, direct or indirect,of RTKs and/or CTKs or the phosphorylation of serine and threonine underthe influence, direct or indirect, of STKs.

[0140] The term “contacting” as used herein refers to bringing acompound of this invention and a target PK together in such a mannerthat the compound can affect the catalytic activity of the PK, eitherdirectly, i.e., by interacting with the kinase itself, or indirectly,i.e., by interacting with another molecule on which the catalyticactivity of the kinase is dependent. Such “contacting” can beaccomplished in vitro, i.e., in a test tube, a petri dish or the like.In a test tube, contacting may involve only a compound and a PK ofinterest or it may involve whole cells. Cells may also be maintained orgrown in cell culture dishes and contacted with a compound in thatenvironment. In this context, the ability of a particular compound toaffect a PK related disorder, i.e., the IC₅₀ of the compound, definedbelow, can be determined before use of the compounds in vivo with morecomplex living organisms is attempted. For cells outside the organism,multiple methods exist, and are well-known to those skilled in the art,to get the PKs in contact with the compounds including, but not limitedto, direct cell microinjection and numerous transmembrane carriertechniques.

[0141] “In vitro” refers to procedures performed in an artificialenvironment such as, e.g., without limitation, in a test tube or culturemedium. The skilled artisan will understand that, for example, anisolated PK may be contacted with a modulator in an in vitroenvironment. Alternatively, an isolated cell may be contacted with amodulator in an in vitro environment.

[0142] As used herein, “in vivo” refers to procedures performed within aliving organism such as, without limitation, a mouse, rat, rabbit,ungulate, bovine, equine, porcine, canine, feline, primate, or human.

[0143] As used herein, “PK related disorder,” “PK driven disorder,” and“abnormal PK activity” all refer to a condition characterized byinappropriate, i.e., under or, more commonly, over, PK catalyticactivity, where the particular PK can be an RTK, a CTK or an STK.Inappropriate catalytic activity can arise as the result of either: (1)PK expression in cells which normally do not express PKs, (2) increasedPK expression leading to unwanted cell proliferation, differentiationand/or growth, or, (3) decreased PK expression leading to unwantedreductions in cell proliferation, differentiation and/or growth.Over-activity of a PK refers to either amplification of the geneencoding a particular PK or production of a level of PK activity whichcan correlate with a cell proliferation, differentiation and/or growthdisorder (that is, as the level of the PK increases, the severity of oneor more of the symptoms of the cellular disorder increases).Under-activity is, of course, the converse, wherein the severity of oneor more symptoms of a cellular disorder increase as the level of the PKactivity decreases.

[0144] As used herein, the terms “prevent”, “preventing” and“prevention” refer to a method for barring an organism from acquiring aPK related disorder in the first place.

[0145] As used herein, the terms “treat”, “treating” and “treatment”refer to a method of alleviating or abrogating a PK mediated cellulardisorder and/or its attendant symptoms. With regard particularly tocancer, these terms simply mean that the life expectancy of anindividual affected with a cancer will be increased or that one or moreof the symptoms of the disease will be reduced.

[0146] The term “organism” refers to any living entity comprised of atleast one cell. A living organism can be as simple as, for example, asingle eukaryotic cell or as complex as a mammal. In a preferred aspect,the organism is a mammal. In a particularly preferred aspect, the mammalis a human being.

[0147] The term “therapeutically effective amount” as used herein refersto that amount of the compound being administered which will relieve tosome extent one or more of the symptoms of the disorder being treated.In reference to the treatment of cancer, a therapeutically effectiveamount refers to that amount which has the effect of (1) reducing thesize of the tumor, (2) inhibiting (that is, slowing to some extent,preferably stopping) tumor metastasis, (3) inhibiting to some extent(that is, slowing to some extent, preferably stopping) tumor growth,and/or, (4) relieving to some extent (or, preferably, eliminating) oneor more symptoms associated with the cancer.

[0148] By “monitoring” is meant observing or detecting the effect ofcontacting a compound with a cell expressing a particular PK. Theobserved or detected effect can be a change in cell phenotype, in thecatalytic activity of a PK or a change in the interaction of a PK with anatural binding partner. Techniques for observing or detecting sucheffects are well-known in the art. For example, the catalytic activityof a PK may be observed by determining the rate or amount ofphosphorylation of a target molecule.

[0149] “Cell phenotype” refers to the outward appearance of a cell ortissue or the biological function of the cell or tissue. Examples,without limitation, of a cell phenotype are cell size, cell growth, cellproliferation, cell differentiation, cell survival, apoptosis, andnutrient uptake and use. Such phenotypic characteristics are measurableby techniques well-known in the art.

[0150] A “natural binding partner” refers to a polypeptide that binds toa particular PK in a cell. Natural binding partners can play a role inpropagating a signal in a PK-mediated signal transduction process. Achange in the interaction of the natural binding partner with the PK canmanifest itself as an increased or decreased concentration of thePK/natural binding partner complex and, as a result, in an observablechange in the ability of the PK to mediate signal transduction.

[0151] As used herein, “administer” or “administration” refers to thedelivery of a compound or salt of the present invention or of apharmaceutical composition containing a compound or salt of thisinvention to an organism for the purpose of prevention or treatment of aPK-related disorder.

[0152] A “pharmaceutical composition” refers to a mixture of one or moreof the compounds described herein, or pharmaceutically acceptable saltsor prodrugs thereof, with other chemical components, such aspharmaceutically acceptable excipients. The purpose of a pharmaceuticalcomposition is to facilitate administration of a compound to anorganism.

[0153] “Pharmaceutically acceptable excipient” refers to an inertsubstance added to a pharmaceutical composition to further facilitateadministration of a compound. Examples, without limitation, ofexcipients include calcium carbonate, calcium phosphate, various sugarsand types of starch, cellulose derivatives, gelatin, vegetable oils andpolyethylene glycols.

[0154] “Pharmaceutically acceptable salt” refers to those salts, whichretain the biological effectiveness and properties of the parentcompound. Such salts include:

[0155] (1) acid addition salt which is obtained by reaction of the freebase of the parent compound with inorganic acids such as hydrochloricacid, hvdrobromic acid, nitric acid, phosphoric acid, sulfuric acid, andperhcloric acid and the like, or with organic acids such as acetic acid,oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaricacid, citric acid, succinic acid or malonic acid and the like,preferably hydrochloric acid or (L)-malic acid; or

[0156] (2) salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

[0157] The compound of Formula (I) may also act as a prodrug. A“prodrug” refers to an agent, which is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent drug is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. An example, without limitation, of a prodrug wouldbe a compound of the present invention, which is, administered as anester (the “prodrug”), carbamate or urea.

[0158] Indications

[0159] The PKs whose catalytic activity is modulated by the compounds ofthis invention include protein tyrosine kinases of which there are twotypes, receptor tyrosine kinases (RTKs) and cellular tyrosine kinases(CTKs), and serine-threonine kinases (STKs). RTK mediated signaltransduction, is initiated by extracellular interaction with a specificgrowth factor (ligand), followed by receptor dimerization, transientstimulation of the intrinsic protein tyrosine kinase activity andphosphorylation. Binding sites are thereby created for intracellularsignal transduction molecules and lead to the formation of complexeswith a spectrum of cytoplasmic signaling molecules that facilitate theappropriate cellular response (e.g., cell division, metabolic effects onthe extracellular microenvironment, etc.). See, Schlessinger andUllrich, Neuron, 9:303-391 (1992).

[0160] It has been shown that tyrosine phosphorylation sites on growthfactor receptors function as high-affinity binding sites for SH2 (srchomology) domains of signaling molecules. Fantl et al., Cell, 69:413-423(1992), Songyang et al., Mol. Cell. Biol., 14:2777-2785 (1994), Songyanget al., Cell, 72:767-778 (1993), and Koch et al., Science, 252:668-678(1991). Several intracellular substrate proteins that associate withRTKs have been identified. They may be divided into two principalgroups: (1) substrates that have a catalytic domain, and (2) substrateswhich lack such domain but which serve as adapters and associate withcatalytically active molecules. Songyang et al., Cell, 72:767-778(1993). The specificity of the interactions between receptors and SH2domains of their substrates is determined by the amino acid residuesimmediately surrounding the phosphorylated tyrosine residue. Differencesin the binding affinities between SH2 domains and the amino acidsequences surrounding the phosphotyrosine residues on particularreceptors are consistent with the observed differences in theirsubstrate phosphorylation profiles. Songyang et al., Cell, 72:767-778(1993). These observations suggest that the function of each RTK isdetermined not only by its pattern of expression and ligand availabilitybut also by the array of downstream signal transduction pathways thatare activated by a particular receptor. Thus, phosphorylation providesan important regulatory step which determines the selectivity ofsignaling pathways recruited by specific growth factor receptors, aswell as differentiation factor receptors.

[0161] STKs, being primarily cytosolic, affect the internal biochemistryof the cell, often as a down-line response to a PTK event. STKs havebeen implicated in the signaling process which initiates DNA synthesisand subsequent mitosis leading to cell proliferation.

[0162] Thus, PK signal transduction results in, among other responses,cell proliferation, differentiation, growth and metabolism. Abnormalcell proliferation may result in a wide array of disorders and diseases,including the development of neoplasia such as carcinoma, sarcoma,glioblastoma and hemangioma, disorders such as leukemia, psoriasis,arteriosclerosis, arthritis and diabetic retinopathy and other disordersrelated to uncontrolled angiogenesis and/or vasculogenesis.

[0163] A precise understanding of the mechanism by which the compoundsof the invention, in particular, the compounds generated in vivo fromthe compounds of the invention, inhibit PKs is not required in order topractice the present invention. However, while not hereby being bound toany particular mechanism or theory, it is believed that the compoundsinteract with the amino acids in the catalytic region of PKs. PKstypically possess a bi-lobate structure wherein ATP appears to bind inthe cleft between the two lobes in a region where the amino acids areconserved among PKs. Inhibitors of PKs are believed to bind bynon-covalent interactions such as hydrogen bonding, van der Waals forcesand ionic interactions in the same general region where the aforesaidATP binds to the PKs. More specifically, it is thought that the2-indolinone component of the compounds of this invention binds in thegeneral space normally occupied by the adenine ring of ATP. Specificityof a particular molecule for a particular PK may then arise as theresult of additional interactions between the various substituents onthe 2-indolinone core and the amino acid domains specific to particularPKs. Thus, different indolinone substituents may contribute topreferential binding to particular PKs. The ability to select compoundsactive at different ATP (or other nucleotide) binding sites makes thecompounds of this invention useful for targeting any protein with such asite. The compounds disclosed herein may thus have utility as in vitroassays for such proteins as well as exhibiting in vivo therapeuticeffects through interaction with such proteins.

[0164] In another aspect, the protein kinase, the catalytic activity ofwhich is modulated by contact with a compound of this invention, is aprotein tyrosine kinase, more particularly, a receptor protein tyrosinekinase. Among the receptor protein tyrosine kinases whose catalyticactivity can be modulated with a compound of this invention, or saltthereof, are, without limitation, selected from the group consisting ofMet, Flk, FGFR, PDGFR, HER, IR, IGF, IRR, CSFIR, C-Kit, C-fins, flt. Ina preferred aspect, the receptor protein tyrosine kinases whosecatalytic activity can be modulated with a compound of this invention,or salt thereof, are, without limitation, Met, Flk-IR, Flk4, KDR/Flk-1,FGFR-1R, FGFR-2R, FGFR-3R, FGFR-4R, PDGFRα, PDGFRβ, HER2, HER3, HER4,IRR, CSFIR, C-Kit and C-fms, preferably Met.

[0165] The protein tyrosine kinase whose catalytic activity is modulatedby contact with a compound of this invention, or a salt thereof, canalso be a non-receptor or cellular protein tyrosine kinase (CTK). Thus,the catalytic activity of CTKs such as, without limitation, Src, Frk,Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk,Hck, Fgr, Aur2 and Yrk may be modulated by contact with a compound orsalt of this invention.

[0166] Still another group of PKs which may have their catalyticactivity modulated by contact with a compound of this invention are theserine-threonine protein kinases such as, without limitation, CDK2, Raf,NEK (including NEK 4a, NEK 4b, NEK 5 and NEK 6) and BUB1.

[0167] In another aspect, this invention relates to a method fortreating or preventing a PK related disorder by administering atherapeutically effective amount of a compound of this invention, or asalt thereof, to an organism.

[0168] It is also an aspect of this invention that a pharmaceuticalcomposition containing a compound of this invention, or a salt thereof,is administered to an organism for the purpose of preventing or treatinga PK related disorder.

[0169] This invention is therefore directed to compounds that modulatePK signal transduction by affecting the enzymatic activity of RTKs, CTKsand/or STKs, thereby interfering with the signals transduced by suchproteins. More particularly, the present invention is directed tocompounds which modulate RTK, CTK and/or STK mediated signaltransduction pathways as a therapeutic approach to cure many kinds ofsolid tumors, including but not limited to carcinomas, sarcomasincluding Kaposi's sarcoma, erythroblastoma, glioblastoma, meningioma,astrocytoma, melanoma and myoblastoma. Treatment or prevention ofnon-solid tumor cancers such as leukemia are also contemplated by thisinvention. Indications may include, but are not limited to braincancers, bladder cancers, ovarian cancers, gastric cancers, pancreascancers, colon cancers, blood cancers, lung cancers and bone cancers.

[0170] Further examples, without limitation, of the types of disordersrelated to inappropriate PK activity that the compounds described hereinmay be useful in preventing, treating and studying, are cellproliferative disorders, fibrotic disorders, metabolic disorders andinfectious diseases.

[0171] Cell proliferative disorders, which may be prevented, treated orfurther studied by the present invention include cancer, blood vesselproliferative disorders and mesangial cell proliferative disorders.

[0172] Blood vessel proliferative disorders refer to disorders relatedto abnormal vasculogenesis (blood vessel formation) and angiogenesis(spreading of blood vessels). While vasculogenesis and angiogenesis playimportant roles in a variety of normal physiological processes such asembryonic development, corpus luteum formation, wound healing and organregeneration, they also play a pivotal role in cancer development wherethey result in the formation of new capillaries needed to keep a tumoralive. Other examples of blood vessel proliferation disorders includearthritis, where new capillary blood vessels invade the joint anddestroy cartilage, and ocular diseases, like diabetic retinopathy, wherenew capillaries in the retina invade the vitreous, bleed and causeblindness.

[0173] Two structurally related RTKs have been identified to bind VEGFwith high affinity: the fms-like tyrosine 1 (fit-l) receptor (Shibuya etal., Oncogene, 5:519-524 (1990); De Vries et al., Science, 255:989-991(1992) and the KDR/FLK-1 receptor, also known as VEGF—R2. Vascularendothelial growth factor (VEGF) has been reported to be an endothelialcell specific mitogen with in vitro endothelial cell growth promotingactivity. Ferrara & Henzel, Biochem. Biophys. Res. Comm., 161:851-858(1989); Vaisman et al., J. Biol. Chem., 265:19461-19566 (1990).Information set forth in U.S. application Ser. Nos. 08/193,829,08/038,596 and 07/975,750, strongly suggest that VEGF is not onlyresponsible for endothelial cell proliferation, but also is the primeregulator of normal and pathological angiogenesis. See generally,Klagsburn & Soker, Current Biology, 3(10):699-702 (1993); Houck, et al.,J. Biol. Chem., 267:26031-26037 (1992).

[0174] Normal vasculogenesis and angiogenesis play important roles in avariety of physiological processes such as embryonic development, woundhealing, organ regeneration and female reproductive processes such asfollicle development in the corpus luteum during ovulation and placentalgrowth after pregnancy. Folkman & Shing, J. Biological Chem.,267(16):10931-10934 (1992). Uncontrolled vasculogenesis and/orangiogenesis has been associated with diseases such as diabetes as wellas with malignant solid tumors that rely on vascularization for growth.Klagsburn & Soker, Current Biology, 3(10):699-702 (1993); Folkham, J.Natl. Cancer Inst., 82:4-6 (1991); Weidner, et al., New Engl. J Med.,324:1-5 (1991).

[0175] As presently understood, the role of VEGF in endothelial cellproliferation and migration during angiogenesis and vasculogenesisindicates an important role for the KDR/FLK-b 1 receptor in theseprocesses. Diseases such as diabetes mellitus (Folkman, 198, in XIthCongress of Thrombosis and Haemostasis (Verstraeta, et al., eds.), pp.583-596, Leuven University Press, Leuven) and arthritis, as well asmalignant tumor growth may result from uncontrolled angiogenesis. Seee.g., Folkman, N. Engl. J Med., 285:1182-1186 (1971). The receptors towhich VEGF specifically binds are an important and powerful therapeutictarget for the regulation and modulation of vasculogenesis and/orangiogenesis and a variety of severe diseases which involve abnormalcellular growth caused by such processes. Plowman, et al., DN&P,7(6):334-339 (1994). More particularly, the KDR/FLK-1 receptor's highlyspecific role in neovascularization make it a choice target fortherapeutic approaches to the treatment of cancer and other diseaseswhich involve the uncontrolled formation of blood vessels.

[0176] Thus, one aspect of the present invention relates to compoundscapable of regulating and/or modulating tyrosine kinase signaltransduction including KDR/FLK- 1 receptor signal transduction in orderto inhibit or promote angiogenesis and/or vasculogenesis, that is,compounds that inhibit, prevent, or interfere with the signal transducedby KDR/FLK- 1 when activated by ligands such as VEGF. Although it isbelieved that the compounds of the present invention act on a receptoror other component along the tyrosine kinase signal transductionpathway, they may also act directly on the tumor cells that result fromuncontrolled angiogenesis.

[0177] Although the nomenclature of the human and murine counterparts ofthe generic “flk-1” receptor differ, they are, in many respects,interchangeable. The murine receptor, Flk-1, and its human counterpart,KDR, share a sequence homology of 93.4% within the intracellular domain.Likewise, murine FLK-1 binds human VEGF with the same affinity as mouseVEGF, and accordingly, is activated by the ligand derived from eitherspecies. Millauer et al., Cell, 72:835-846 (1993); Quinn et al., Proc.Natl. Acad. Sci. USA, 90:7533-7537 (1993). FLK-1 also associates withand subsequently tyrosine phosphorylates human RTK substrates (e.g.,PLC-γ or p85) when co-expressed in 293 cells (human embryonal kidneyfibroblasts).

[0178] Models which rely upon the FLK-b 1 receptor therefore aredirectly applicable to understanding the KDR receptor. For example, useof the murine FLK-1 receptor in methods which identify compounds thatregulate the murine signal transduction pathway are directly applicableto the identification of compounds which may be used to regulate thehuman signal transduction pathway, that is, which regulate activityrelated to the KDR receptor. Thus, chemical compounds identified asinhibitors of KDR/FLK-1 in vitro, can be confirmed in suitable in vivomodels. Both in vivo mouse and rat animal models have been demonstratedto be of excellent value for the examination of the clinical potentialof agents acting on the KDRIFLK-1 induced signal transduction pathway.

[0179] Thus, in one aspect, this invention is directed to compounds thatregulate, modulate and/or inhibit vasculogenesis and/or angiogenesis byaffecting the enzymatic activity of the KDR/FLK-1 receptor andinterfering with the signal transduced by KDR/FLK-1. In another aspect,the present invention is directed to compounds which regulate, modulateand/or inhibit the KDR/FLK-1 mediated signal transduction pathway as atherapeutic approach to the treatment of many kinds of solid tumorsincluding, but not limited to, glioblastoma, melanoma and Kaposi'ssarcoma, and ovarian, lung, mammary, prostate, pancreatic, colon andepidermoid carcinoma. In addition, data suggest the administration ofcompounds which inhibit the KDR/Flk-1 mediated signal transductionpathway may also be used in the treatment of hemangioma, restenois anddiabetic retinopathy.

[0180] A further aspect of this invention relates to the inhibition ofvasculogenesis and angiogenesis by other receptor-mediated pathways,including the pathway comprising the flt-1 receptor.

[0181] Receptor tyrosine kinase mediated signal transduction isinitiated by extracellular interaction with a specific growth factor(ligand), followed by receptor dimerization, transient stimulation ofthe intrinsic protein tyrosine kinase activity and autophosphorylation.Binding sites are thereby created for intracellular signal transductionmolecules which leads to the formation of complexes with a spectrum ofcytoplasmic signaling molecules that facilitate the appropriate cellularresponse, e.g., cell division and metabolic effects to the extracellularmicroenvironment. See, Schlessinger and Ullrich, Neuron, 9:1-20 (1992).

[0182] The close homology of the intracellular regions of KDR/FLK-1 withthat of the PDGF-β receptor (50.3% homology) and/or the related flt-1receptor indicates the induction of overlapping signal transductionpathways. For example, for the PDGF-β receptor, members of the srcfamily (Twamley et al., Proc. Natl. Acad. Sci. USA, 90:7696-7700(1993)), phosphatidylinositol-3′-kinase (Hu et al., Mol. Cell. Biol.,12:981-990 (1992), phospholipase cγ (Kashishian & Cooper, Mol. Cell.Biol., 4:49-51 (1993)), ras-GTPase-activating protein, (Kashishian etal., EMBO J, 11:1373-1382 (1992), PTP-ID/syp (Kazlauskas et al., Proc.Natl. Acad. Sci. USA, 90:6939-6943 (1993)), Grb2 (Arvidsson et al., Mol.Cell. BioL, 14:6715-6726 (1994)), and the adapter molecules Shc and Nck(Nishimura et al., Mol. Cell. Biol., 13:6889-6896 (1993)), have beenshown to bind to regions involving different autophosphorylation sites.See generally, Claesson-Welsh, Prog. Growth Factor Res., 5:37-54 (1994).Thus, it is likely that signal transduction pathways activated byKDR/FLK-1 include the ras pathway (Rozakis et al., Nature, 360:689-692(1992)), the PI-3′-kinase, the src-mediated and the plcγ-mediatedpathways. Each of these pathways may play a critical role in theangiogenic and/or vasculogenic effect of KDR/FLK-1 in endothelial cells.Consequently, a still further aspect of this invention relates to theuse of the organic compounds described herein to modulate angiogenesisand vasculogenesis as such processes are controlled by these pathways.

[0183] Conversely, disorders related to the shrinkage, contraction orclosing of blood vessels, such as restenosis, are also implicated andmay be treated or prevented by the methods of this invention.

[0184] Fibrotic disorders refer to the abnormal formation ofextracellular matrices. Examples of fibrotic disorders include hepaticcirrhosis and mesangial cell proliferative disorders. Hepatic cirrhosisis characterized by the increase in extracellular matrix constituentsresulting in the formation of a hepatic scar. An increased extracellularmatrix resulting in a hepatic scar can also be caused by a viralinfection such as hepatitis. Lipocytes appear to play a major role inhepatic cirrhosis. Other fibrotic disorders implicated includeatherosclerosis.

[0185] Mesangial cell proliferative disorders refer to disorders broughtabout by abnormal proliferation of mesangial cells. Mesangialproliferative disorders include various human renal diseases such asglomerulonephritis, diabetic nephropathy and malignant nephrosclerosisas well as such disorders as thrombotic microangiopathy syndromes,transplant rejection, and glomerulopathies. The RTK PDGFR has beenimplicated in the maintenance of mesangial cell proliferation. Floege etal., Kidney International, 43:47S-54S (1993).

[0186] Many cancers are cell proliferative disorders and, as notedpreviously, PKs have been associated with cell proliferative disorders.Thus, it is not surprising that PKs such as, for example, members of theRTK family have been associated with the development of cancer. Some ofthese receptors, like EGFR (Tuzi et al., Br. J Cancer, 63:227-233(1991), Torp et al., APMIS, 100:713-719 (1992)) HER2/neu (Slamon et al.,Science, 244:707-712 (1989)) and PDGF-R (Kumabe et al., Oncogene,7:627-633 (1992)) are over-expressed in many tumors and/or persistentlyactivated by autocrine loops. In fact, in the most common and severecancers these receptor over-expressions (Akbasak and Suner-Akbasak etal., J Neurol. Sci., 111:119-133 (1992), Dickson et al., CancerTreatment Res., 61:249-273 (1992), Korc et al., J. Clin. Invest.,90:1352-1360 (1992)) and autocrine loops (Lee and Donoghue, J. Cell.Biol., 118:1057-1070 (1992), Korc et al., supra, Akbasak andSuner-Akbasak et al., supra) have been demonstrated. For example, EGFRhas been associated with squamous cell carcinoma, astrocytoma,glioblastoma, head and neck cancer, lung cancer and bladder cancer. HER2has been associated with breast, ovarian, gastric, lung, pancreas andbladder cancer. PDGFR has been associated with glioblastoma and melanomaas well as lung, ovarian and prostate cancer. The RTK c-met has alsobeen associated with malignant tumor formation. For example, c-met hasbeen associated with, among other cancers, colorectal, thyroid,pancreatic, gastric and hepatocellular carcinomas and lymphomas.Additionally c-met has been linked to leukemia. Over-expression of thec-met gene has also been detected in patients with Hodgkins disease andBurkitts disease.

[0187] IGF-IR, in addition to being implicated in nutritional supportand in type-II diabetes, has also been associated with several types ofcancers. For example, IGF-I has been implicated as an autocrine growthstimulator for several tumor types, e.g. human breast cancer carcinomacells (Arteaga et al., J Clin. Invest., 84:1418-1423 (1989)) and smalllung tumor cells (Macauley et al., Cancer Res., 50:2511-2517 (1990)). Inaddition, IGF-I, while integrally involved in the normal growth anddifferentiation of the nervous system, also appears to be an autocrinestimulator of human gliomas. Sandberg-Nordqvist et al., Cancer Res.,53:2475-2478 (1993). The importance of IGF-IR and its ligands in cellproliferation is further supported by the fact that many cell types inculture (fibroblasts, epithelial cells, smooth muscle cells,T-lymphocytes, myeloid cells, chondrocytes and osteoblasts (the stemcells of the bone marrow)) are stimulated to grow by IGF-I. Goldring andGoldring, Eukaryotic Gene Expression, 1:301-326 (1991). In a series ofrecent publications; Baserga suggests that IGF-IR plays a central rolein the mechanism of transformation and, as such, could be a preferredtarget for therapeutic interventions for a broad spectrum of humanmalignancies. Baserga, Cancer Res., 55:249-252 (1995), Baserga, Cell,79:927-930 (1994), Coppola et al, Mol. Cell. Biol., 14:4588-4595 (1994).

[0188] STKs have been implicated in many types of cancer including,notably, breast cancer (Cance, et al., Int. J Cancer, 54:571-77 (1993)).

[0189] The association between abnormal PK activity and disease is notrestricted to cancer. For example, RTKs have been associated withdiseases such as psoriasis, diabetes mellitus, endometriosis,angiogenesis, atheromatous plaque development, Alzheimer's disease, vonHippel-Lindau disease, epidermal hyperproliferation, neurodegenerativediseases, age-related macular degeneration and hemangiomas. For example,EGFR has been indicated in corneal and dermal wound healing. Defects inInsulin-R and IGF-1R are indicated in type-II diabetes mellitus. A morecomplete correlation between specific RTKs and their therapeuticindications is set forth in Plowman et al., DN&P, 7:334-339 (1994).

[0190] As noted previously, not only RTKs but CTKs including, but notlimited to, src, abl, fps, yes, fyn, lyn, lck, blk, hck, fgr and yrk(reviewed by Bolen et al., FASEB J, 6:3403-3409 (1992)) are involved inthe proliferative and metabolic signal transduction pathway and thuscould be expected, and have been shown, to be involved in manyPTK-mediated disorders to which the present invention is directed. Forexample, mutated src (v-src) has been shown to be an oncoprotein(pp60^(v-src)) in chicken. Moreover, its cellular homolog, theproto-oncogene pp60^(c-src) transmits oncogenic signals of manyreceptors. Over-expression of EGFR or HER2/neu in tumors leads to theconstitutive activation of pp60^(c src), which is characteristic ofmalignant cells but absent in normal cells. On the other hand, micedeficient in the expression of c-src exhibit an osteopetrotic phenotype,indicating a key participation of c-src in osteoclast function and apossible involvement in related disorders.

[0191] Similarly, Zap70 has been implicated in T-cell signaling whichmay relate to autoimmune disorders.

[0192] STKs have been associated with inflammation, autoimmune disease,immunoresponses, and hyperproliferation disorders such as restenosis,fibrosis, psoriasis, osteoarthritis and rheumatoid arthritis.

[0193] PKs have also been implicated in embryo implantation. Thus, thecompounds of this invention may provide an effective method ofpreventing such embryo implantation and thereby be useful as birthcontrol agents.

[0194] In yet another aspect, the compounds of the instant invention canalso be used as anti-infective agents. For example, indolinone compoundsare known to exhibit antibacterial and antifungal activities. See, e.g.,Singh and Jha, “Indolinone derivatives as potential antimicrobialagents,” Zentralbl. Mikrobiol,. 144(2):105-109 (1989). In addition,indolinone compounds have been reported to exhibit significant antiviralactivity. See, e.g., Maass et al., “Viral resistance to thethiazolo-iso-indolinones, a new class of nonnucleoside inhibitors ofhuman immunodeficiency virus type I reverse transcriptase,” Antimicrob.Agents Chemother., 37(12):2612-2617 (1993).

[0195] Finally, both RTKs and CTKs are currently suspected as beinginvolved in hyperimmune disorders.

[0196] A method for identifying a chemical compound that modulates thecatalytic activity of one or more of the above discussed protein kinasesis another aspect of this invention. The method involves contactingcells expressing the desired protein kinase with a compound of thisinvention (or its salt) and monitoring the cells for any effect that thecompound has on them. The effect may be any observable, either to thenaked eye or through the use of instrumentation, change or absence ofchange in a cell phenotype. The change or absence of change in the cellphenotype monitored may be, for example, without limitation, a change orabsence of change in the catalytic activity of the protein kinase in thecells or a change or absence of change in the interaction of the proteinkinase with a natural binding partner.

[0197] Pharmaceutical Compositions and Use

[0198] A compound of the present invention or a physiologicallyacceptable salt thereof, can be administered as such to a human patientor can be administered in pharmaceutical compositions in which theforegoing materials are mixed with suitable carriers or excipient(s).Techniques for formulation and administration of drugs may be found in“Remington's Pharmacological Sciences,” Mack Publishing Co., Easton,Pa., latest edition.

[0199] Routes of Administration

[0200] Suitable routes of administration may include, withoutlimitation, oral, intraoral, rectal, transmucosal or intestinaladministration or intramuscular, epicutaneous, parenteral, subcutaneous,transdermal, intramedullary, intrathecal, direct intraventricular,intravenous, intravitreal, intraperitoneal, intranasal, intramuscular,intradural, intrarespiratory, nasal inhalation or intraocularinjections. The preferred routes of administration are oral andparenteral.

[0201] Alternatively, one may administer the compound in a local ratherthan systemic manner, for example, via injection of the compounddirectly into a solid tumor, often in a depot or sustained releaseformulation.

[0202] Furthermore, one may administer the drug in a targeted drugdelivery system, for example, in a liposome coated with tumor-specificantibody. The liposomes will be targeted to and taken up selectively bythe tumor.

[0203] Composition/Formulation

[0204] Pharmaceutical compositions of the present invention may bemanufactured by processes well known in the art, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping, lyophilizing processes or spraydrying.

[0205] Pharmaceutical compositions for use in the methods of the presentinvention may be prepared by any methods of pharmacy, but all methodsinclude the step of bringing in association the active ingredient withthe carrier which constitutes one or more necessary ingredients. Inparticular, pharmaceutical compositions for use in accordance with thepresent invention may be formulated in conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

[0206] Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, patches, syrups, elixirs, gels, powders, magmas,lozenges, ointments, creams, pastes, plasters, lotions, discs,suppositories, nasal or oral sprays, aerosols and the like.

[0207] For injection, the compounds of the invention may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch buffers with or without a low concentration of surfactant orcosolvent, or physiological saline buffer. For transmucosaladministration, penetrants appropriate to the barrier to be permeatedare used in the formulation. Such penetrants are generally known in theart.

[0208] For oral administration, the compounds can be formulated bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, lozenges, dragees,capsules, liquids, gels, syrups, slurries, suspensions and the like, fororal ingestion by a patient. Pharmaceutical preparations for oral usecan be made using a solid excipient, optionally grinding the resultingmixture, and processing the mixture of granules, after adding othersuitable auxiliaries if desired, to obtain tablets or dragee cores.Useful excipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol, cellulose preparations such as,for example, maize starch, wheat starch, rice starch and potato starchand other materials such as gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl- cellulose, sodium carboxymethylcellulose, and/orpolyvinyl- pyrrolidone (PVP). If desired, disintegrating agents may beadded, such as cross-linked polyvinyl pyrrolidone, agar, or alginicacid. A salt such as sodium alginate may also be used.

[0209] Dragee cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses.

[0210] Pharmaceutical compositions which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with a fillersuch as lactose, a binder such as starch, and/or a lubricant such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, liquid polyethyleneglycols, cremophor, capmul, medium or long chain mono- di- ortriglycerides. Stabilizers may be added in these formulations, also.

[0211] For administration by inhalation, the compounds for use accordingto the present invention are conveniently delivered in the form of anaerosol spray using a pressurized pack or a nebulizer and a suitablepropellant, e.g., without limitation, dichlorodifluoromethane,trichlorofluoromethane, dichlorotetra- fluoroethane or carbon dioxide.In the case of a pressurized aerosol, the dosage unit may be controlledby providing a valve to deliver a metered amount. Capsules andcartridges of, for example, gelatin for use in an inhaler or insufflatormay be formulated containing a powder mix of the compound and a suitablepowder base such as lactose or starch.

[0212] The compounds may also be formulated for parenteraladministration, e.g., by bolus injection or continuous infusion.Formulations for injection may be presented in unit dosage form, e.g.,in ampoules or in multi-dose containers, with an added preservative. Thecompositions may take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles, and may contain formulating materials suchas suspending, stabilizing and/or dispersing agents.

[0213] Pharmaceutical compositions for parenteral administration includeaqueous solutions of a water soluble form, such as, without limitation,a salt, of the active compound. Additionally, suspensions of the activecompounds may be prepared in a lipophilic vehicle. Suitable lipophilicvehicles include fatty oils such as sesame oil, synthetic fatty acidesters such as ethyl oleate and triglycerides, or materials such asliposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers and/or agents that increase the solubilityof the compounds to allow for the preparation of highly concentratedsolutions.

[0214] Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile, pyrogen-free water,before use.

[0215] The compounds may also be formulated in rectal compositions suchas suppositories or retention enemas, using, e.g., conventionalsuppository bases such as cocoa butter or other glycerides.

[0216] In addition to the formulations described previously, thecompounds may also be formulated as depot preparations. Such long actingformulations may be administered by implantation (for example,subcutaneously or intramuscularly) or by intramuscular injection. Acompound of this invention may be formulated for this route ofadministration with suitable polymeric or hydrophobic materials (forinstance, in an emulsion with a pharmacologically acceptable oil), withion exchange resins, or as a sparingly soluble derivative such as,without limitation, a sparingly soluble salt.

[0217] A non-limiting example of a pharmaceutical carrier for thehydrophobic compounds of the invention is a cosolvent system comprisingbenzyl alcohol, a nonpolar surfactant, a water-miscible organic polymerand an aqueous phase such as the VPD co-solvent system. VPD is asolution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactantPolysorbate 80™, and 65% w/v polyethylene glycol 300, made up to volumein absolute ethanol. The VPD co-solvent system (VPD:D5W) consists of VPDdiluted 1:1 with a 5% dextrose in water solution. This co-solvent systemdissolves hydrophobic compounds well, and itself produces low toxicityupon systemic administration. Naturally, the proportions of such aco-solvent system may be varied considerably without destroying itssolubility and toxicity characteristics. Furthermore, the identity ofthe co-solvent components may be varied: for example, zotherlow-toxicity nonpolar surfactants may be used instead of Polysorbate80™, the fraction size of polyethylene glycol may be varied, otherbiocompatible polymers may replace polyethylene glycol, e.g., polyvinylpyrrolidone, and other sugars or polysaccharides may substitute fordextrose.

[0218] Alternatively, other delivery systems for hydrophobicpharmaceutical compounds may be employed. Liposomes and emulsions arewell known examples of delivery vehicles or carriers for hydrophobicdrugs. In addition, certain organic solvents such as dimethylsulfoxidealso may be employed, although often at the cost of greater toxicity.

[0219] Additionally, the compounds may be delivered using asustained-release system, such as semipermeable matrices of solidhydrophobic polymers containing the therapeutic agent. Varioussustained-release materials have been established and are well known bythose skilled in the art. Sustained-release capsules may, depending ontheir chemical nature, release the compounds for a few weeks up to over100 days. Depending on the chemical nature and the biological stabilityof the therapeutic reagent, additional strategies for proteinstabilization may be employed.

[0220] The pharmaceutical compositions herein also may comprise suitablesolid or gel phase carriers or excipients. Examples of such carriers orexcipients include, but are not limited to, calcium carbonate, calciumphosphate, various sugars, starches, cellulose derivatives, gelatin, andpolymers such as polyethylene glycols.

[0221] Many of the PK modulating compounds of the invention may beprovided as physiologically acceptable salts wherein the claimedcompound may form the negatively or the positively charged species.Examples of salts in which the compound forms the positively chargedmoiety include, without limitation, quaternary ammonium (definedelsewhere herein), salts such as the hydrochloride, sulfate, carbonate,lactate, tartrate, maleate, succinate wherein the nitrogen atom of thequaternary ammonium group is a nitrogen of the selected compound of thisinvention which has reacted with the appropriate acid. Salts in which acompound of this invention forms the negatively charged species include,without limitation, the sodium, potassium, calcium and magnesium saltsformed by the reaction of a carboxylic acid group in the compound withan appropriate base (e.g. sodium hydroxide (NaOH), potassium hydroxide(KOH), Calcium hydroxide (Ca(OH)₂), etc.).

[0222] Dosage

[0223] Pharmaceutical compositions suitable for use in the presentinvention include compositions wherein the active ingredients arecontained in an amount sufficient to achieve the intended purpose, i.e.,the modulation of PK activity or the treatment or prevention of aPK-related disorder.

[0224] More specifically, a therapeutically effective amount means anamount of compound effective to prevent, alleviate or amelioratesymptoms of disease or prolong the survival of the subject beingtreated.

[0225] Determination of a therapeutically effective amount is wellwithin the capability of those skilled in the art, especially in lightof the detailed disclosure provided herein.

[0226] For any compound used in the methods of the invention, thetherapeutically effective amount or dose can be estimated initially fromcell culture assays. Then, the dosage can be formulated for use inanimal models so as to achieve a circulating concentration range thatincludes the IC₅₀ as determined in cell culture (i.e., the concentrationof the test compound which achieves a half-maximal inhibition of the PKactivity). Such information can then be used to more accuratelydetermine useful doses in humans.

[0227] Toxicity and therapeutic efficacy of the compounds describedherein can be determined by standard pharmaceutical procedures in cellcultures or experimental animals, e.g., by determining the IC₅₀ and theLD₅₀ (both of which are discussed elsewhere herein) for a subjectcompound. The data obtained from these cell culture assays and animalstudies can be used in formulating a range of dosage for use in humans.The dosage may vary depending upon the dosage form employed and theroute of administration utilized. The exact formulation, route ofadministration and dosage can be chosen by the individual physician inview of the patient's condition. (See e.g., Fingl, et al., 1975, in “ThePharmacological Basis of Therapeutics”, Ch. 1 p. 1).

[0228] Dosage amount and interval may be adjusted individually toprovide plasma levels of the active species which are sufficient tomaintain the kinase modulating effects. These plasma levels are referredto as minimal effective concentrations (MECs). The MEC will vary foreach compound but can be estimated from in vitro data, e.g., theconcentration necessary to achieve 50-90% inhibition of a kinase may beascertained using the assays described herein. Dosages necessary toachieve the MEC will depend on individual characteristics and route ofadministration. HPLC assays or bioassays can be used to determine plasmaconcentrations.

[0229] Dosage intervals can also be determined using MEC value.Compounds should be administered using a regimen that maintains plasmalevels above the MEC for 10-90% of the time, preferably between 30-90%and most preferably between 50-90%. At present, the therapeuticallyeffective amounts of compounds of Formula (I) may range fromapproximately 25 mg/m² to 150 mg/m² perday. Even more preferably 25mg/m² to 1000 mg/m².

[0230] In cases of local administration or selective uptake, theeffective local concentration of the drug may not be related to plasmaconcentration and other procedures known in the art may be employed todetermine the correct dosage amount and interval.

[0231] The amount of a composition administered will, of course, bedependent on the subject being treated, the severity of the affliction,the manner of administration, the judgment of the prescribing physician,etc.

[0232] Packaging

[0233] The compositions may, if desired, be presented in a pack ordispenser device, such as an FDA approved kit, which may contain one ormore unit dosage forms containing the active ingredient. The pack mayfor example comprise metal or plastic foil, such as a blister pack. Thepack or dispenser device may be accompanied by instructions foradministration. The pack or dispenser may also be accompanied by anotice associated with the container in a form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals, which notice is reflective of approval by the agency ofthe form of the compositions or of human or veterinary administration.Such notice, for example, may be of the labeling approved by the U.S.Food and Drug Administration for prescription drugs or of an approvedproduct insert. Compositions comprising a compound of the inventionformulated in a compatible pharmaceutical carrier may also be prepared,placed in an appropriate container, and labeled for treatment of anindicated condition. Suitable conditions indicated on the label mayinclude treatment of a tumor, inhibition of angiogenesis, treatment offibrosis, diabetes, and the like.

EXAMPLES

[0234] Compound Synthesis

[0235] The compounds of this invention, as well as the precursorindolinones, may be readily synthesized using techniques well known inthe chemical arts. It will be appreciated by those skilled in the artthat other synthetic pathways for forming the compounds of the inventionare available and that the following is offered by way of example andnot limitation.

[0236] The following syntheses of representative compounds of thisinvention are shown by way of example only and are not to be construedas limiting the scope of this invention as to synthetic approach or asto the compounds whose syntheses are exemplified.

[0237] It will be clear to those skilled in the art, based both on knowngeneral principles of organic synthesis and on the disclosures hereinappropriate changes and modifications to the following syntheses thatmay be effected without departing from the scope or spirit of theinvention as defined in the appended claims.

[0238] HPLC data was obtained with a Zorbax SB C18 column (4.6 mm ID+7.5cm), a Perkin Elmer series 200 pump programmed to run from 10%acetonitrile/water 0.1% TFA (solvent A) to 90% acetonitrile/water(solvent B) with a flow rate of 1.5 mL/min. After 0.1 min on solvent A,a 5 min linear program to solvent B was run, followed by 3 min onsolvent B, before recycling to solvent A (2 min). Detection was with aPerkin Elmer diode array detector recording at 215 and 280 nM). NMRspectra were recorded on a Bruker instrument at 300 MHz.

[0239] A. General synthetic procedure.

[0240] The following general methodology may be employed to prepare thecompounds of this invention:

[0241] The appropriately substituted 2-oxindole (1 equiv.), theappropriately substituted aldehyde (1.2 equiv.) and a base (0.1 equiv.)are mixed in a solvent (1-2 ml/mmol 2-oxindole) and the mixture is thenheated for from about 2 to about 12 hours. After cooling, theprecipitate that forms is filtered, washed with cold ethanol or eitherand vacuum dried to give the solid product. If no precipitate forms, thereaction mixture is concentrated and the residue is triturated withdichloromethane/ether, the resulting solid is collected by filtrationand then dried. The product may optionally be further purified bychromatography.

[0242] The base may be an organic or an inorganic base. If an organicbase is used, preferably it is a nitrogen base. Examples of organicnitrogen bases include, but are not limited to, diusopropylamine,trimethylamine, triethylamine, aniline, pyridine, 1,8-diazabicyclo[5.4.1 ]undec-7-ene, pyrrolidine and piperidine.

[0243] Examples of inorganic bases are, without limitation, ammonia,alkali metal or alkaline earth hydroxides, phosphates, carbonates,bicarbonates, bisulfates and amides. The alkali metals include, lithium,sodium and potassium while the alkaline earths include calcium,magnesium and barium.

[0244] In a presently preferred aspect of this invention, when thesolvent is a protic solvent, such as water or alcohol, the base is analkali metal or an alkaline earth inorganic base, preferably, a alkalimetal or an alkaline earth hydroxide.

[0245] It will be clear to those skilled in the art, based both on knowngeneral principles of organic synthesis and on the disclosures hereinwhich base would be most appropriate for the reaction contemplated.

[0246] The solvent in which the reaction is carried out may be a proticor an aprotic solvent, preferably it is a protic solvent. A “proticsolvent” is a solvent which has hydrogen atom(s) covalently bonded tooxygen or nitrogen atoms which renders the hydrogen atoms appreciablyacidic and thus capable of being “shared” with a solute through hydrogenbonding. Examples of protic solvents include, without limitation, waterand alcohols.

[0247] An “aprotic solvent” may be polar or non-polar but, in eithercase, does not contain acidic hydrogens and therefore is not capable ofhydrogen bonding with solutes. Examples, without limitation, ofnon-polar aprotic solvents, are pentane, hexane, benzene, toluene,methylene chloride and carbon tetrachloride. Examples of polar aproticsolvents are chloroform, tetrahydro- furan, dimethylsulfoxide anddimethylformamide.

[0248] In a presently preferred aspect of this invention, the solvent isa protic solvent, preferably water or an alcohol such as ethanol.

[0249] The reaction is carried out at temperatures greater than roomtemperature. The temperature is generally from about 30° C. to about150° C., preferably about 80° C. to about 100° C., most preferable about75° C. to about 85° C., which is about the boiling point of ethanol. By“about” is meant that the temperature range is preferably within 10degrees Celsius of the indicated temperature, more preferably within 5degrees Celsius of the indicated temperature and, most preferably,within 2 degrees Celsius of the indicated temperature. Thus, forexample, by “about 75° C.” is meant 75° C.±10° C., preferably 75° C.±5°C. and most preferably, 75° C.±2° C.

[0250] B. General Procedures for the Syntheses of 4-Aryl-1H-indole.

[0251] Procedure A:

[0252] Preparation of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole.

[0253] To a mixture of 4-bromoindole (1, 9.80 g, 50 mmol), pinacolediborate (2, 13.97 g, 55 mmol), and KOAc (14.72 g, 150 mmol) in DMSO(200 mL) was added Palladium catalyst PdCl₂(dppf)CH₂Cl₂ (1.22 g, 1.5mmol). The system was degassed, and then charged with nitrogen for threetimes. The mixture was stirred at 80° C. oil bath under nitrogen for 22hours. TLC² showed the complete disappearance of the starting material4-bromoindole (1). The mixture was cooled to room temperature, and thenpoured to water (1 L). The product was extracted with ethyl acetate forthree times. The combined extracts were washed by brine for five timesto remove DMSO solvent, and then dried over Na₂SO₄. During the washingstep, the catalyst may precipitate out, which was removed by filtration.The ethyl acetate solution was filtered and condensed. The residue waspurified on a silica gel column eluting with EtOAc-hexane (9:1). Thefirst fraction provided the side product indole (1.25 g, 21% yield),R_(f) 0.55 (EtOAc-Hexane 5:1). The second fraction provided the product4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole as a whitesolid (3, 8.01 g, 66%), R_(f) 0.46 (EtOAc-Hexane 5:1).

[0254]¹H NMR (300 MHz, DMSO-d₆) δ 11.03 (bs, 1H, N-H)),7.49 (d, J7.7 Hz,1H, H-5), 7.38 (dd, J0.9 Hz, J7.0 Hz, 1H, H-7), 7.38 (t, J2.6 Hz, 1H,H-2), 7.06 (dd, J7.7 Hz, J7.0 Hz, 1H, H-6),6.73 (bd, J2.2 Hz, 1H, H-3),1.32 (s, 12H, 4CH₃).

[0255] MS m/z 244 [M⁺+1].

[0256] Preparation of 4-Aryl-1H-Indole.

[0257] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 1 molarequivalent), and aryl bromide (4, 1.01 molar equivalent) in THF (0.3 M))were added Palladium catalyst Pd(PPh₃)₄ (0.03 molar equivalent) and thefreshly prepared sodium hydroxide solution (2.76N, 3 equivalent). Thesystem was degassed and then charged with nitrogen. The degas procedurewas repeated for three times. The mixture was stirred under nitrogen at70° C. oil bath for 6 - 24 hours. TLC showed the completion of thecoupling reaction. The mixture was cooled to room temperature, dilutedwith ethyl acetate, and separated from water layer. The ethyl acetatesolution was washed by brine, and dried over Na₂SO₄. After filtration,the solvents were evaporated, and the crude product was purified by asilica gel column.

[0258] Procedure B:

[0259] Preparation of 4-Aryl-1H-Indole.

[0260] To a mixture of 4-bromoindole (1 molar equivalent), and arylboronic acid (1 molar equivalent) in THF (0.3 M)) were added Palladiumcatalyst Pd(PPh₃)₄ (0.03 molar equivalent) and the freshly preparedsodium hydroxide solution (2.76N, 3 equivalent). The system was degassedand then charged with nitrogen. The degas procedure was repeated forthree times. The mixture was stirred under nitrogen at 70° C. oil bathfor 6 - 24 hours. TLC showed the completion of the coupling reaction.The mixture was cooled to room temperature, diluted with ethyl acetate,and separated from water layer. The ethyl acetate solution was washed bybrine, and dried over Na₂SO₄. After filtration, the solvents wereevaporated, and the crude product was purified by a silica gel column.

Example A-1 4-Phenyl-1H-indole

[0261]

[0262] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (pinacole4-indoleboronate (2 g, 8.2 mnmol) and 3-bromobenzene (0.87 mL, 8.3 mmol)in THF (28 mL) were added Palladium catalyst Pd(PPh₃)₄ (284 mg, 0.25mmol) and the freshly prepared sodium hydroxide solution (984 mg in 9 mLof water). The system was degassed and then charged with nitrogen forthree times. The mixture was stirred under nitrogen at 70 C. oil bathfor 6 hours. The reaction solution was cooled to room temperature,diluted with ethyl acetate and separated from water layer. The ethylacetate solution was washed by brine, dried over Na₂SO₄ andconcentrated. The residue was purified on a silica gel column elutingwith hexanes: EtOAc 9:1 to give 1.38 g (78%) of 4-phenyl-1H-indole as acolorless liquid.

[0263]¹H NMR (360 MHz, DMSO-d₆) δ 11.26 (br s, 1H, NH), 7.66 (d, J=7.9Hz, 2H), 7.50 (t, J=7.5 Hz, 2H), 7.35-7.43 (m, 3H), 7.18 (t, J=7.5 Hz,1H), 7.08 (d, J=7.1 Hz, 1H),6.41 (brs, 1H).

[0264] MS m/z 194 [M⁺+1].

Example A-2 4-(4-Fluoro-phenyl)-1H-indole

[0265]

[0266] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 4.0 g,16.4 mmol), and 4-bromofluorobenzene (3.45 g, 19.7 mmol) in THF (80 mL))were added Palladium catalyst Pd(PPh₃)₄ (0.57 g, 0.49 mmol) and thefreshly prepared sodium hydroxide solution (2.0 g, 49.3 mmol in 25 mLwater). The system was degassed and then charged with nitrogen. Thedegas procedure was repeated for three times. The mixture was stirredunder nitrogen at 70° C. oil bath for 15 hours. TLC showed thecompletion of the coupling reaction. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and separated from water layer.The ethyl acetate solution was washed by brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by a silica gel columneluting with hexanes—EtOAc (9:1) to provide 2.75 g (80%) of the product4-(4-fluoro-phenyl)-1H-indole as a white solid.

[0267]¹H-NMR (400 MHz, DMSO-d₆) δ 11.26 (br s, 1H, NH), 7.68 (m, 2H,aromatic), 7.41 (m, 2H, aromatic), 7.32 (m, 2H aromatic), 7.17 (m, 1H,aromatic), 7.05 (m, 1H, aromatic), 6.51 (m, 1H, aromatic).

[0268] MS m/z 212 [M⁺+1].

Example A-3 4-(3-Fluoro-phenyl)-1H-indole

[0269]

[0270] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g,10 mmol), and 3-bromofluorobenzene (1.09 mL, 10 mmol) in THF (34 mL))were added Palladium catalyst Pd(PPh₃)₄ (347 mg, 0.3 mmol) and thefreshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mLwater). The system was degassed and then charged with nitrogen. Thedegas procedure was repeated for three times. The mixture was stirredunder nitrogen at 70° C. oil bath for 15 hours. TLC showed thecompletion of the coupling reaction. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and separated from water layer.The ethyl acetate solution was washed by brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by a silica gel columneluting with hexanes—EtOAc (9:1) to provide 1.88 g (88%) of the product4-(3-fluoro-phenyl)-1H-indole as a colorless syrup.

[0271]¹H-NMR (400 MHz, DMSO-d₆) δ 11.30 (br s, 1H, NH), 7.52 (m, 2H,aromatic), 7.45 (m, 3H, aromatic), 7.20 (m, 2H, aromatic), 7.12 (m, 1H,aromatic), 6.55 (m, 1H, aromatic).

[0272] MS m/z 212 [M⁺+1].

Example A-4 4-(4-Chloro-phenyl)-1H-indole

[0273]

[0274] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g,10 mmol), and 4-bromochlorobenzene (2.87 g, 15 mmol) in THF (34 mL))were added Palladium catalyst Pd(PPh₃)₄ (347 mg, 0.3 mmol) and thefreshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mLwater). The system was degassed and then charged with nitrogen. Thedegas procedure was repeated for three times. The mixture was stirredunder nitrogen at 70° C. oil bath for 15 hours. TLC showed thecompletion of the coupling reaction. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and separated from water layer.The ethyl acetate solution was washed by brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by a silica gel columneluting with hexanes—EtOAc (9:1) to provide 2.02 g (89%) of the product4-(4-chloro-phenyl)-1H-indole as a white solid.

[0275]¹H-NMR (400 MHz, DMSO-d₆) δ 11.29 (br s, 1H, NH), 7.70 (m, 2H,aromatic), 7.55 (m, 2H, aromatic), 7.43 (m, 2H, aromatic), 7.19 (t, 1H,aromatic), 7.08 (m, 1H aromatic), 6.53 (m, 1H, aromatic).

Example A-5 4-(3-Chloro-phenyl)-1H-indole

[0276]

[0277] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g,10 mmol), and 3-bromochlorobenzene (1.76 mL, 15 mmol) in THF (34 mL))were added Palladium catalyst Pd(PPh₃)₄ (347 mg, 0.3 mmol) and thefreshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mLwater). The system was degassed and then charged with nitrogen. Thedegas procedure was repeated for three times. The mixture was stirredunder nitrogen at 70° C. oil bath for 15 hours. TLC showed thecompletion of the coupling reaction. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and separated from water layer.The ethyl acetate solution was washed by brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by a silica gel columneluting with hexanes—EtOAc (9:1) to provide 2.06 g (91%) of the product4-(3-chloro-phenyl)-1H-indole as a white solid.

[0278]¹H-NMR (400 MHz, DMSO-d,) δ 11.32 (br s, 1H, NH), 7.66 (m, 2H,aromatic), 7.53 (t, 1H, aromatic), 7.45 (m, 3H, aromatic), 7.20 (t, 1H,aromatic), 7.11 (d, 1H, aromatic), 6.53 (d, 1H, aromatic).

Example A-6 4-(4-Bromo-phenyl)-1H-indole

[0279]

[0280] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g,10 mmol), and 1,4-dibromobenzene (11.8 g, 50 mmol) in THF (34 mL)) wereadded Palladium catalyst Pd(PPh₃)₄ (347 mg, 0.3 mmol) and the freshlyprepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). Thesystem was degassed and then charged with nitrogen. The degas procedurewas repeated for three times. The mixture was stirred under nitrogen at70° C. oil bath for 15 hours. TLC showed the completion of the couplingreaction. The mixture was cooled to room temperature, diluted with ethylacetate, and separated from water layer. The ethyl acetate solution waswashed by brine, dried over Na₂SO₄, and concentrated. The crude productwas purified by a silica gel column eluting with hexanes—EtOAc (9:1) toprovide 1.50 g (55%) of the product 4-(4-bromo-phenyl)-1H-indole as awhite solid.

[0281]¹H-NMR (400 MHz, DMSO-d₆) δ 11.29 (br s, 1H, NH), 7.65 (m, 4H,aromatic), 7.41 (m, 2H, aromatic), 7.17 (t, 1H, aromatic), 7.08 (m, 1H,aromatic), 6.51 (m, 1H, aromatic).

Example A-7 4-(3-Bromo-phenyl)-1H-indole

[0282]

[0283] To a mixture of 4-(4,4,5 ,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)- 1H-indole (3, 2.43 g, 10 mmol), and1,4-dibromobenzene (11.8 g, 5 0 mmol) in THF (34 mL)) were addedPalladium catalyst Pd(PPh₃)₄ (347 mg, 0.3 mmol) and the freshly preparedsodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The systemwas degassed and then charged with nitrogen. The degas procedure wasrepeated for three times. The mixture was stirred under nitrogen at 70°C. oil bath for 15 hours. TLC showed the completion of the couplingreaction. The mixture was cooled to room temperature, diluted with ethylacetate, and separated from water layer. The ethyl acetate solution waswashed by brine, dried over Na₂SO₄, and concentrated. The crude productwas purified by a silica gel column eluting with hexanes—EtOAc (9:1) toprovide 2.02 g (74%) of the product 4-(3-bromo-phenyl)-1H-indole as awhite solid.

[0284]¹H-NMR(400 MHz, DMSO-d₆) δ 11.33 (brs, 1H, NH),7.80 (m, 1H,aromatic), 7.68 (d, 1H, aromatic), 7.57 (m, 1H, aromatic), 7.45 (m, 3H,aromatic), 7.19 (t, 1H, aromatic), 7.10 (d, 1H, aromatic), 6.52 (m, 1H,aromatic).

[0285] MS m/z 271, 273 [M++1].

Example A-8 4-(4-Methoxy-phenyl)-1H-indole

[0286]

[0287] To a mixture of 4-bromoindole (1.96 g, 10 mmol), and4-methoxyphenylboronic acid (1.52 g, 10 mmol) in THF (34 mL)) were addedPalladium catalyst Pd(PPh₃)₄ (347 mg, 0.3 mmol) and the freshly preparedsodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The systemwas degassed and then charged with nitrogen. The degas procedure wasrepeated for three times. The mixture was stirred under nitrogen at 70°C. oil bath for 16 hours. TLC showed the completion of the couplingreaction. The mixture was cooled to room temperature, diluted with ethylacetate, and separated from water layer. The ethyl acetate solution waswashed by brine, dried over Na₂SO₄, and concentrated. The crude productwas purified by a silica gel column eluting with hexanes—EtOAc (9:1) toprovide 1.85 g (83%) of the product 4-(4-Methoxy-phenyl)-1H-indole as awhite solid.

[0288]¹H-NMR (400 MHz, DMSO-d₆) δ 11.21 (br s, 1H, NH), 7.61 (m, 2H,aromatic), 7.38 (m, 2H, aromatic), 7.15 (t, 1H, aromatic), 7.05 (m, 3H,aromatic), 6.52 (m, 1H, aromatic), 3.30 (s, 3H, CH₃).

[0289] MS m/z 224 [M⁺+1].

Example A-9 4-(3-Methoxy-phenyl)-1H-indole

[0290]

[0291] To a mixture of 4-bromoindole (1.96 g, 10 mmol), and3-methoxyphenylboronic acid (1.52 g, 10 mmol) in THF (34 mL)) were addedPalladium catalyst Pd(PPh₃)₄ (347 mg, 0.3 mmol) and the freshly preparedsodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The systemwas degassed and then charged with nitrogen. The degas procedure wasrepeated for three times. The mixture was stirred under nitrogen at 70°C. oil bath for 16 hours. TLC showed the completion of the couplingreaction. The mixture was cooled to room temperature, diluted with ethylacetate, and separated from water layer. The ethyl acetate solution waswashed by brine, dried over Na₂SO₄, and concentrated. The crude productwas purified by a silica gel column eluting with hexanes—EtOAc (9:1) toprovide 1.83 g (82%) of the product 4-(3-methoxy-phenyl)-1H-indole ascolorless syrup.

[0292]¹H-NMR (400 MHz, DMSO-d₆) δ 11.26 (br s, 1H, NH), 7.41 (m, 3H,aromatic), 7.25 (d, 1H, aromatic), 7.18 (m, 2H, aromatic), 7.1 1 (d, 1H,aromatic), 6.95 (m, 1H, aromatic), 6.57 (m, 1H, aromatic), 3.82 (s, 3H,CH₃).

[0293] MS m/z 224 [M⁺+1].

Example A-10 4-(2-Fluoro-phenyl)-1H-indole

[0294]

[0295] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.431 g,10.0 mmol), and 2-bromofluorobenzene (1.75 g, 10.1 mmol) in THF (34 mL))were added Palladium catalyst Pd(PPh₃)₄ (0.347 g, 0.30 mmol) and thefreshly prepared sodium hydroxide solution (1.20 g, 30.0 mmol in 14 mLwater). The system was degassed and then charged with nitrogen. Thedegas procedure was repeated for three times. The mixture was stirredunder nitrogen at 75° C. oil bath for 15 hours. TLC showed thecompletion of the coupling reaction. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and separated from water layer.The ethyl acetate solution was washed by brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by a silica gel columneluting with hexanes—EtOAc (9:1) to provide 1.35 g (64%) of the product4-(2-fluoro-phenyl)-1H-indole as a white solid.

[0296]¹H-NMR (400 MHz, DMSO-d₆) δ 11.25 (br s, 1H, NH), 7.55 (m, 1H,aromatic), 7.38 (m, 5H, aromatic), 7.18 (t, 1H, aromatic), 7.03 (d, 1H,aromatic), 6.27 (m, 1H, aromatic).

[0297] MS m/z 212 [M⁺+1].

Example A-11 4-(3-Trifluoromethyl-phenyl)-1H-indole

[0298]

[0299] To a mixture of 4-bromoindole (3.00 g, 15.3 mmol), and3-trifluoromethylphenylboronic acid (2.91 g, 15.3 mmol) in THF (52 mL))were added Palladium catalyst Pd(PPh₃)₄ (530 mg, 0.46 mmol) and thefreshly prepared sodium hydroxide solution (1.84 g, 45.9 mmol in 21 mLwater). The system was degassed and then charged with nitrogen. Thedegas procedure was repeated for three times. The mixture was stirredunder nitrogen at 75° C. oil bath for 16 hours. TLC showed thecompletion of the coupling reaction. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and separated from water layer.The ethyl acetate solution was washed by brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by a silica gel columneluting with hexanes—EtOAc (9:1) to provide 3.55 g (89%) of the product4-(3-trifluoromethyl-phenyl)-1H-indole.

[0300]¹H-NMR (400 MHz, DMSO-d₆) δ 11.40 (br s, 1H, NH), 7.98 (t, 1H,aromatic), 7.95 (s, 1H, aromatic), 7.73 (m, 2H, aromatic), 7.50 (d, 1H,aromatic), 7.47 (t, 1 H, aromatic), 7.22 (t, 1 H, aromatic), 7.16 (d, 1H, aromatic), 6.54 (s, 1 H, aromatic).

[0301] MS m/z 262 [M⁺+1].

Example A-12 4-(3-Chloro4-fuoro-phenyl)-1H-indole

[0302]

[0303] To a mixtureof4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 3.00 g,12.34 mmol), and 4-bromo-2-chloro-fluorobenzene (2.58 g, 12.34 mmol) inTHF (42 mL)) were added Palladium catalyst Pd(PPh₃)₄ (0.428 g, 0.37mmol) and the freshly prepared sodium hydroxide solution (1.50 g, 37.02mmol in 17 mL water). The system was degassed and then charged withnitrogen. The degas procedure was repeated for three times. The mixturewas stirred under nitrogen at 75° C. oil bath for 15 hours. TLC showedthe completion of the coupling reaction. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and separated from water layer.The ethyl acetate solution was washed by brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by a silica gel columneluting with hexanes—EtOAc (9:1) to provide 2.11 g (70%) of the product4-(3-chloro-4-fluoro-phenyl)-1H-indole as a white solid.

[0304]¹H-NMR (400 MHz, DMSO-d₆) δ 11.34 (br s, 1H, NH), 7.79 (dd, 1H,aromatic), 7.67 (m, 1H, aromatic), 7.53 (t, 1H, aromatic), 7.44 (m, 2H,aromatic), 7.19 (t, 1H, aromatic), 7.10 (d, 1H, aromatic), 6.52 (m, 1H,aromatic).

[0305] MS m/z 244 [M⁺+1].

Example A-13 4-(3-Trifluoromethoxy-phenyl)-1H-indole

[0306]

[0307] To a mixture of 4-bromoindole (4.50 g, 22.95 mmol), and4-trifluoromethoxyphenylboronic acid (4.73 g, 22.95 mmol) in THF (78mL)) were added Palladium catalyst Pd(PPh₃)₄ (795.6 mg, 0.69 mmol) andthe freshly prepared sodium hydroxide solution (2.75 g, 68.9 mmol in 32mL water). The system was degassed and then charged with nitrogen. Thedegas procedure was repeated for three times. The mixture was stirredunder nitrogen at 75° C. oil bath for 16 hours. TLC showed thecompletion of the coupling reaction. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and separated from water layer.The ethyl acetate solution was washed by brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by a silica gel columneluting with hexanes—EtOAc (9:1) to provide 5.56 g (78%) of the product4-(4-trifluoromethoxy-phenyl)-1H-indole.

[0308]¹H-NMR (400 MHz, DMSO-d₆) δ 11.32 (br s, 1H, NH), 7.78 (d, 2H,aromatic), 7.45 (m, 4H, aromatic), 7.20 (t, 1H, aromatic), 7.10 (d, 1H,aromatic), 6.55 (m, 1H, aromatic).

[0309] MS m/z 278 [M⁺+1].

Example A-14 2-Fluoro-5-(1H-indol-4-yl)-benzonitrile

[0310]

[0311] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (4 g, 16.4mmol), and 5-bromo-2-fluorobenzonitrile (3.28 g, 16.4 mmol) in THF (564mL) were added Palladium catalyst Pd(PPh₃)₄ (0.6 g, 0.5 mmol) and thefreshly prepared sodium carbonate solution (5.22 g in 23 mL of water).The system was degassed and then charged with nitrogen. The degasprocedure was repeated for three times. The mixture was stirred undernitrogen at 83 ° C. oil bath for overnight. TLC showed the completion ofthe coupling reaction. The mixture was cooled to room temperature,diluted with ethyl acetate, and separated from water layer. The ethylacetate solution was washed with brine, and dried over Na₂SO₄. Afterfiltration, the solvents were evaporated, and the crude product waspurified by a silica gel column to give 2.18 g (56%) of2-fluoro-5-(1H-indol-4-yl)-benzonitrile.

Example A-15 4-Biphenyl-3-yl-1H-indole

[0312]

[0313] To a mixture of 4-bromoindole (2.1 g, 10 mmol), and3-biphenylboronic acid (2.2 g, 10 mmol) in THF (34.5 mL) were addedPalladium catalyst Pd(PPh₃)₄ (0.35 g, 0.3 mmol) and the freshly preparedsodium hydroxide solution (1.21 g, 30 mmol in 14 mL of water). Thesystem was degassed and then charged with nitrogen. The degas procedurewas repeated for three times. The mixture was stirred under nitrogen at75° C. oil bath for overnight. TLC showed the completion of the couplingreaction. The mixture was cooled to room temperature, diluted with ethylacetate, and separated from water layer. The ethyl acetate solution waswashed with brine, and dried over Na₂SO₄. After filtration, the solventswere evaporated, and the crude product was purified on a silica gelcolumn to give 4-biphenyl-3-yl-1H-indole.

Example A-16 4-Biphenyl-2-yl-1H-indole

[0314]

[0315] To a mixture of 4-bromoindole (1 g, 5 mmol), and2-biphenylboronic acid (1 g, 5 mmol) in THF (17 mL) were added Palladiumcatalyst Pd(PPh₃)₄ (0.2 g, 0.17 mmol) and the freshly prepared sodiumhydroxide solution (0.6 g, 15 mmol in 7 mL of water). The system wasdegassed and then charged with nitrogen. The degas procedure wasrepeated for three times. The mixture was stirred under nitrogen at 75°C. oil bath for overnight. TLC showed the completion of the couplingreaction. The mixture was cooled to room temperature, diluted with ethylacetate, and separated from water layer. The ethyl acetate solution waswashed with brine, and dried over Na₂SO₄. After filtration, the solventswere evaporated, and the crude product was purified on a silica gelcolumn to give 1.26 g (93%) of 4-biphenyl-2-yl-1H-indole.

Example A-17 4-(3,5-Difluoro-phenyl)-1H-indole

[0316]

[0317] To a mixture of 4-bromoindole (12.42 g, 63.3 mmol), and3,5-difluorophenylboronic acid (10.0 g, 63.3 mmol) in THF (108 mL) wereadded Palladium catalyst Pd(PPh₃)₄ (2.2 g, 1.9 mmol) and the freshlyprepared sodium hydroxide solution (7.6 g, 190 mmol in 89 mL water). Thesystem was degassed and then charged with nitrogen. The degas procedurewas repeated for three times. The mixture was stirred under nitrogen at85° C. oil bath for overnight. TLC showed the completion of the couplingreaction. The mixture was cooled to room temperature, filtered throughcelite, diluted with ethyl acetate, and separated from water layer. Theethyl acetate solution was washed with brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by a silica gel column toprovide 4-(3,5-difluoro-phenyl)- 1 H-indole.

Example A-18 [3-(1H-Indol-4-yl)-phenyl]-acetic acid

[0318]

[0319] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (15.52 g,63.72 mmol), and 3-bromo-phenylacetic acid (13.78 g, 63.72 mmol) in THF(192 mL) were added Palladium catalyst Pd(PPh₃)₄ (2.21 g, 1.9 mmol) andthe freshly prepared sodium hydroxide solution (7.65 g in 90 mL ofwater). The system was degassed and then charged with nitrogen. Thedegas procedure was repeated for three times. The mixture was stirredunder nitrogen in a 70 ° C. oil bath for over the weekend. TLC showedthe completion of the coupling reaction. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and separated from water layer.The water layer was acidified with dil. HCl solution to pH 4-5 andextracted with ethyl acetate. The ethyl acetate solution was washed withwater, brine, and dried over Na₂SO₄. After filtration, the solvents wereevaporated, and the crude product was purified on a silica gel column togive 13.5 g (84%) of [3-(1H-indol-4-yl)-phenyl]-acetic acid.

Example A-19 2-[3-(1H-Indol-4-yl)-phenyl]-NN-dimethyl-acetamide

[0320]

[0321] Dimethylamine (2M in THF, 5 mL) was added to a mixture of[3-(1H-indol-4-yl)-phenyl]-acetic acid (1.26 g, 5 mmol), EDC (1.19 g,1.25 eq.) and HOBt (675 mg, 1 eq.) in THF (10 mL) was stirred at rt for5 hours. The reaction was concentrated, diluted with ethyl acetate,washed with 10% Na₂CO₃ (3x), brine, dried and concentrated. The residuewas purified on a silica gel column to give 658 mg of2-[3-(1H-iIndol-4-yl)-phenyl]-N,N-dimethyl-acetamide as a solid.

Example A-20 {2-[3-( 1 H-Indol4-yl)-phenyl]-ethyl}-dimethyl-amine

[0322]

[0323] To a suspension of LAH (276 mg, 7.2 mmol) in THF (20 mL) undernitrogen at rt was added dropwise a solution of2-[3-(1H-indol-4-yl)-phenyl]-N,N-dimethyl-acetamide (500 mg, 1.8 mmol)in THF (10 mL). After stirring at rt for 6 hours, the reaction wasquenched with water (0.6 mL) dropwise. The precipitate was filtered off,washed with ethyl acetate (3×), the filtrate was concentrated t give 640mg of {2-[3-(1 H-indol-4-yl)-phenyl]-ethyl } -dimethyl-amine.

Example A-21 5-(1H-Indol-4-yl)-1H-indazol-3-ylamine

[0324]

[0325] Hydrazine hydrate (0.4 mL, 12.7 mmol) was added to a solution of2-fluoro-5-(1H-indol-4-yl)-benzonitrile (1.2 g, 5.08 mmol) in n-butanol(25 mL). The mixture was heated to reflux under nitrogen for 3 days. Thereaction was cooled to room temperature and the solvent was removed. Theresidue was purified on a silica gel column eluting with DCM:MeOH (95:5)to give 1.05 g (83%) of 5-(1H-indol-4-yl)-1H-indazol-3-ylamine as awhite foam.

[0326]¹H-NMR (400 MHz, DMSO-d₆) δ 11.40 (s, 1 H, NH), 11.18 (s, 1 H,NH), 7.96 (s,1H), 7.54 (dd, 1H), 7.29-7.38 (m, 3H), 7.14 (t, 1H), 7.05(d, 1H), 6.58 (s, 1H), 5.4 (br s, 2H, NH₂).

[0327] MS m/z 249 [M⁺+1].

Example A-22 4-(2,6-Difluoro-phenyl)-1H-indole

[0328]

[0329] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (11.34 g,46.6 mmol), and 1-bromo-2,6-difluorobenzene (9 g, 46.6 mmol) in1,2-dimethoxyethane (204 mL) were added Palladium catalyst Pd(PPh₃)₄(1.62 g, 1.4 mmol) and the freshly prepared sodium carbonate solution(15.19 g in 66 mL of water). The system was degassed and then chargedwith nitrogen. The degas procedure was repeated for three times. Themixture was stirred under nitrogen at 110° C. oil bath for overnight.TLC showed the completion of the coupling reaction. The mixture wascooled to room temperature, diluted with ethyl acetate, and separatedfrom water layer. The ethyl acetate solution was washed with brine, anddried over Na₂SO₄. After filtration, the solvents were evaporated, andthe crude product was purified by a silica gel column to give 9.77 g(91%) of 4-(2,6-difluoro-phenyl)-1H-indole.

Example A-23 3-(1H-iIndol-4-yl)-benzoic acid

[0330]

[0331] To a mixture of 4-bromoindole (11.81 g, 60.26 mmol), and3-carboxyphenylboronic acid (10.0 g, 60.6 mmol) in acetonitrile (100 mL)and DMF (100 mL) were added Palladium catalyst Pd(PPh₃)₄ (2.09 g, 1. 81mmol) and the freshly prepared sodium hydroxide solution (9.64 g, 241mmol in 80 mL water). The system was degassed and then charged withnitrogen. The degas procedure was repeated for three times. The mixturewas stirred under argon at 110° C. oil bath for 4 hours. TLC showed thecompletion of the coupling reaction. The mixture was cooled to roomtemperature, filtered through celite, diluted with ethyl acetate, andseparated from water layer. The ethyl acetate solution was washed withbrine, dried over MgSO₄, and concentrated. The crude product waspurified by a silica gel column eluting with DCM:Hexanes:acetic acid(100:1:1) to provide 10.2 g (71%) of 3-(1H-indol-4-yl)-benzoic acid as agray yellow solid.

[0332]¹H-NMR (400 MHz, DMSO-d₆) δ 13.02 (s, 1H, NH), 11.31 (s, 1H),8.21-8.26 (m, 1H), 7.87-7.97 (m, 2H), 7.58-7.65 (m, 1H), 7.41-7.45 (m,2H), 7.08-7.22 (m, 2H), 6.51 (br s, 1H).

[0333] MS m/z 238 [M⁺+1].

Example A-24 4-(3,4-Dimethoxy-phenyl)-1H-indole

[0334]

[0335] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (10 g, 41.1mmol), and 4-bromoveratrole (8.93 g, 41.1 mmol) in THF (140 mL) wereadded Palladium catalyst Pd(PPh₃)₄ (1.43 g, 1.23 mmol) and the freshlyprepared sodium hydroxide solution (5.08 g in 58 mL of water). Thesystem was degassed and then charged with nitrogen. The degas procedurewas repeated for three times. The mixture was stirred under nitrogen at80° C. oil bath for overnight. TLC showed the completion of the couplingreaction. The mixture was cooled to room temperature, diluted with ethylacetate, and separated from water layer. The ethyl acetate solution waswashed with brine, and dried over Na₂SO₄. After filtration, the solventswere evaporated, and the crude product was purified by a silica gelcolumn to give 7.47 g (72%) of 4-(3,4-dimethoxy-phenyl)-1H-indole.

Example A-25 2-[3-(1H-Indol4-yl)-phenoxy]-ethanol

[0336]

[0337] A mixture of 3-bromo-phenol (10 g, 56.64 mmol), 2-bromoethanol(4.65 mL) and cesium carbonate (18.64 g, 1 eq.) in DMF (25 mL) wasstirred at rt for overnight. The mixture was then heated in a 70 ° C.oil bath for about 3 hours. More 2-bromoethanol (3 mL) was added andheating was increased to 80° C. and stirred for overnight. The reactionwas allowed to cool to rt and the insolubles were filtered off. Thefiltrate was poured into water and extracted with ethyl acetate (2×200mL), washed with 10% Na₂CO₃ (3×), brine (2×), dried and concentrated.The residue was purified on a silica gel column to give2-(3-bromo-phenoxy)-ethanol.

[0338] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (5.49 g, 22.5mmol) and 2-(3-bromo-phenoxy)-ethanol (4.9 g, 22.5 mmol) in THF (68 mL)was added Palladium catalyst Pd(PPh₃)₄ (473 mg, 0.03 eq.) and thefreshly prepared sodium hydroxide solution (2.7 g in 31.5 mL of water).The system was degassed and then charged with nitrogen. The degasprocedure was repeated for three times. The mixture was stirred undernitrogen at 70 ° C. oil bath for overnight. TLC showed the completion ofthe coupling reaction. The mixture was cooled to room temperature,diluted with ethyl acetate, and separated from water layer. The ethylacetate solution was washed with brine (4×), and dried over Na₂SO₄ andconcentrated. The residue was purified on a silica gel column to give5.4 g (95%) of 2-[3-(1H-indol-4-yl)-phenoxy]-ethanol.

[0339]¹H-NMR (400 MHz, CDCl₃) δ 8.35 (br s, 1H, NH), 7.39 (m, 2H), 7.32(m, 1H), 7.28 (m, 2H), 7.24 (m, 1H), 7.19 (dd, 1H), 6.93 (m, 1H), 6.73(m, 1H), 4.15 (m, 3H), 4.0 (m, 2H).

[0340] MS m/z 254 [M⁺+1].

Example A-26 4-(2,3-Difluoro-phenyl)-1H-indole

[0341]

[0342] To a mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3.78 g, 15.5mmol), and 1-bromo-2,3-difluorobenzene (3 g, 15.5 mmol) in THF (55 mL)were added Palladium catalyst Pd(PPh₃)₄ (0.54 g, 0.47 mmol) and thefreshly prepared sodium hydroxide solution (1.865 g, 47 mmol in 22 mL ofwater). The system was degassed and then charged with nitrogen. Thedegas procedure was repeated for three times. The mixture was stirredunder nitrogen at 75° C. oil bath for overnight. TLC showed thecompletion of the coupling reaction. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and separated from water layer.The ethyl acetate solution was washed with brine, and dried over Na₂SO₄.After filtration, the solvents were evaporated, and the crude productwas purified by a silica gel column to give 2.92 g (82%) of4-(2,3-difluoro-phenyl)-1H-indole.

Example A-27 4-(2,4-Difluorophenyl)-1H-indole

[0343]

[0344] To a mixture of 4-bromoindole (6.2 g, 31.7 mmol), and2,4-difluorophenylboronic acid (5 g, 31.7 mmol) in THF (108 mL) wereadded Palladium catalyst Pd(PPh₃)₄ (0.67 g, 0.95 mmol) and the freshlyprepared sodium hydroxide solution (3.8 g, 95 mmol in 45 mL of water).The system was degassed and then charged with nitrogen. The degasprocedure was repeated for three times. The mixture was stirred undernitrogen at 80° C. oil bath for over the weekend. TLC showed thecompletion of the coupling reaction. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and separated from water layer.The ethyl acetate solution was washed with brine, and dried over Na₂SO₄.After filtration, the solvents were evaporated, and the crude productwas purified by a silica gel column to give 6.55 g (90%) of4-(2,4-difluoro-phenyl)-1H-indole.

Example A-28 4-(2-Chloro-phenyl)-1H-indole

[0345]

[0346] To a mixture of 4-bromoindole (5.5 g, 28 mmol), and2-chlorophenylboronic acid (4.4 g, 28 mmol) in THF (96 mL) were addedPalladium catalyst Pd(PPh₃)₄ (0.975 g, 0.8 mmol) and the freshlyprepared sodium hydroxide solution (3.4 g, 84 mmol in 40 mL of water).The system was degassed and then charged with nitrogen. The degasprocedure was repeated for three times. The mixture was stirred undernitrogen at 75° C. oil bath for overnight. TLC showed the completion ofthe coupling reaction. The mixture was cooled to room temperature,diluted with ethyl acetate, and separated from water layer. The ethylacetate solution was washed with brine, and dried over Na₂SO₄. Afterfiltration, the solvents were evaporated, and the crude product waspurified by a silica gel column to give 2.41 g (38%) of4-(2-chloro-phenyl)- 1H-indole.

Example A-29 [3-(1H-Indol-4-yl)-phenyl]-acetic acid methyl ester

[0347]

[0348] A mixture of [3-(1H-indol-4-yl)-phenyl]-acetic acid (4 g, 15.9mmol), 4N HCl (20 drops) in methanol (30 mL) and dioxane was stirred atrt for 4 hours. The reaction was concentrated, diluted in ethyl acetate,washed with NaHCO₃ (2×), brine (2×), dried and concentrated to give 3.72g (88%) of [3-(1H-Indol-4-yl)-phenyl]-acetic, acid methyl ester.

[0349] General Procedure for the Syntheses of the Precursor,4-Aryl-1,3-dihydro-indol-2-one

[0350] To the suspension of 4-aryl-1H-indole (1 molar equivalent) in2-methyl-2- propanol—ethanol—acetic acid (3:2:1) (11 mL) (0.1 M) wasadded pyridinium tribromide (90% purity from Aldrich, 3 molarequivalent) portionwise. The mixture was stirred at 27° C. for 3 hours,and then to the mixture was added acetic acid. Zinc dust (10 molarequivalent) was added to the reaction mixture portionwise, and thereaction mixture was stirred at room temperature for one hour. Theunreacted zinc dust was filtered off and washed with ethanol. Thefiltrate was concentrated and the syrupy residue was suspended in waterfor 1 hour. The solid product was precipitated out, filtered, and washedrepeatedly with water to remove the zinc salt and pyridine salt. Afterhigh vacuum dry, a pure product was obtained. If the product couldn'tprecipitate out, ethyl acetate was used to extract the product fromwater. The combined extracts were washed with water, 0.5% HCl watersolution, sat. Na₂CO₃, and brine, dried over Na₂SO₄. After filtration,condensation, the crude product was triturated with diethyl ether toprovide pure product.

Example A-30 4-Phenyl-1,3-dihydro-indol-2-one

[0351]

[0352] To the suspension of 4-phenyl-1H-indole (1.1 g, 5.7 mmol) in2-methyl-2-propanol (33 mL), ethanol (22 mL) and acetic acid (11 mL) wasadded pyridinium tribromide (90% purity from Aldrich, 6.1 g, 17.1 mmol)portionwise over 10 minutes. The mixture was stirred at room temperaturefor 2 hours, and then to the mixture was added acetic acid (50 mL).After stirring at room temperature for one hour, water (0.5 mL) and zinc(3.7 g, 57 mmol) were added to the reaction mixture and stirring wascontinued for another hour. The unreacted zinc dust was filtered off andwashed with methanol. The filtrate was concentrated and the syrupyresidue was suspended in water (100 mL) for overnight. The solid productwas filtered, washed repeatedly with water to remove the zinc salt andpyridine salt. After high vacuum dry, 800 mg (67%) of4-phenyl-1,3-dihydro-indol-2-one as a light yellow solid was obtained.

[0353]¹H NMR (360 MHz, DMSO-d₆) 10.46 (br s, 1H, NH), 7.56 (d, J=7.1 Hz,1H), 7.45 (t, J=7.6 Hz, 1H), 7.37 (m, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.01(d, J=7.7 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 3.59 (s, 2H, CH₂).

[0354] MS m/z 210 [M⁺+1].

Example A-31 4-(4-Fluoro-phenyl)-1,3-dihydro-indol-2-one

[0355]

[0356] To the suspension of 4-(4-fluoro-phenyl)-1H-indole (2.28 g, 10.79mmol) in t-BuOH—ethanol—acetic acid (3:2:1) (147 mL) was addedpyridinium tribromide (90% purity from Aldrich, 11.51 g, 32.38 mmol))portionwise. The mixture was stirred at 27° C. for 3 hours, and then tothe mixture was added acetic acid (108 mL). Zinc dust (10.52 g, 162mmol) was added to the reaction mixture portionwise, and the reactionmixture was stirred at room temperature for one hour. The unreacted zincdust was filtered off and washed with ethanol. The filtrate wasconcentrated and the syrupy residue was suspended in water for 4 hour.The solid product was precipitated out, filtered, and washed repeatedlywith water to remove the zinc salt and pyridine salt. After high vacuumdry, a pure product (2.40 g, 98%) was obtained.

[0357]¹H NMR (360 MHz, DMSO-d₆) 10.47 (br s, 1H, NH), 7.61 (m, 2H,aromatic), 7.27 (m, 3H, aromatic), 7.12 (d, 1H, aromatic), 6.90 (d, 1H,aromatic), 3.59 (s, 2H).

Example A-32. 4-(3-Fluoro-phenyl)-1,3-dihydro-indol-2-one

[0358]

[0359] To the suspension of 4-(3-fluoro-phenyl)-1H-indole (1.40 g, 6.63mmol) in t-BuOH —ethanol—acetic acid (3:2:1) (81 mL) was addedpyridinium tribromide (90% purity from Aldrich, 7.07 g, 19.88 mmol))portionwise. The mixture was stirred at 27° C. for 3 hours, and then tothe mixture was added acetic acid (30 mL). Zinc dust was added to thereaction mixture portionwise until the color changed from deep red tolight yellow, and the reaction mixture was stirred at room temperaturefor one hour. The unreacted zinc dust was filtered off and washed withethanol. The filtrate was concentrated, and the syrupy residue wasdissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat.NaHCO₃ and brine, and dried over Na₂SO₄. After filtration andevaporation, the crude product was triturated with diethyl ether toprovide product 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (1.34 g,89%) as a tan solid.

[0360]¹H-NMR (400 MHz, DMSO-d₆) δ 10.50 (br s, 1H, NH), 7.51(m, 1H,aromatic), 7.47 (m, 2H, aromatic), 7.43 (t, 1H, aromatic), 7.30 (m, 1H,aromatic), 7.22 (d 1H, aromatic), 6.85 (d, 1H, aromatic), 3.64 (s, 2H,CH₂).

Example A-33 4-(4-Chloro-phenyl)- 1,3-dihydro-indol-2-one

[0361]

[0362] To the suspension of 4-(4-chloro-phenyl)-1H-indole (1.52 g, 6.68mmol) in t-BuOH—ethanol—acetic acid (3:2:1) (81 mL) was added pyridiniumtribromide (90% purity from Aldrich, 7.12 g, 20.0 mmol)) portionwise.The mixture was stirred at 27° C. for 3 hours, and then to the mixturewas added acetic acid (30 mL). Zinc dust was added to the reactionmixture portionwise until the color changed from deep red to lightyellow, and the reaction mixture was stirred at room temperature for onehour. The unreacted zinc dust was filtered off and washed with ethanol.The filtrate was concentrated, and the syrupy residue was suspended inwater (500 mL) for 0.5 hour. The solid product was precipitated out,filtered, and washed repeatedly with water to remove the zinc salt andpyridine salt. After high vacuum dry, a pure product (1.54 g, 94%) wasobtained.

[0363]¹H-NMR (400 MHz, DMSO-d₆) δ 11.29 (br s, 1H, NH), 7.70 (m, 2H,aromatic), 7.55 (m, 2H, aromatic), 7.43 (m, 2H, aromatic), 7.19 (t, 1H,aromatic), 7.08 (m, 1H aromatic), 6.53 (m, 1H, aromatic).

Example A-34 4-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one

[0364]

[0365] To the suspension of 4-(3-chloro-phenyl)-1H-indole (1.52 g, 6.68mmol) in t-BuOH—ethanol—acetic acid (3:2:1) (81 mL) was added pyridiniumtribromide (90% purity from Aldrich, 7.12 g, 20.0 mmol)) portionwise.The mixture was stirred at 27° C. for 3 hours, and then to the mixturewas added acetic acid (30 mL). Zinc dust was added to the reactionmixture portionwise until the color changed from deep red to lightyellow, and the reaction mixture was stirred at room temperature for onehour. The unreacted zinc dust was filtered off and washed with ethanol.The filtrate was concentrated, and the syrupy residue was dissolved inethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO₃ andbrine, and dried over Na₂SO₄. After filtration and evaporation, thecrude product was triturated with diethyl ether to provide product4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (1.55 g, 95%) as a tansolid.

[0366]¹H¹H-NMR (400 MHz, DMSO-d₆) δ 10.50 (br s, 1H, NH), 7.62 (m, 1H,aromatic), 7.56 (m, 1H, aromatic), 7.52 (m, 2H, aromatic), 7.29 (t, 1H,aromatic), 7.03 (d, 1H, aromatic), 6.85 (m, 1H, aromatic), 3.63 (s, 2H,CH₂).

Example A-35 4-(4-Bromo-phenyl)- 1,3-dihydro-indol-2-one

[0367]

[0368] To the suspension of 4-(4-bromo-phenyl)-1H-indole (1.20 g, 4.41mmol) in t-BuOH—ethanol—aceticacid (3:2:1) (54 mL) was added pyridiniumtribromide (4.23 g, 13.23 mmol)) portionwise. The mixture was stirred at27° C. for 3 hours, and then to the mixture was added acetic acid (30mL). Zinc dust was added to the reaction mixture portionwise until thecolor changed from deep red to light yellow, and the reaction mixturewas stirred at room temperature for one hour. The unreacted zinc dustwas filtered off and washed with ethanol. The filtrate was concentrated,and the syrupy residue was suspended in water (300 mL) for 0.5 hour. Thesolid product was precipitated out, filtered, and washed repeatedly withwater to remove the zinc salt and pyridine salt. After high vacuum dry,a pure product (1.12 g, 88%) was obtained.

[0369]¹H-NMR (400 MHz, DMSO-d₆) δ 10.50 (br s, 1H, NH), 7.64 (d, 2H,aromatic), 7.54 (d, 2H, aromatic), 7.28 (t, 1H, aromatic), 7.01 (d, 1H,aromatic), 6.84 (d, 1H, aromatic), 3.60 (s, 2H, CH₂).

Example A-36 4-(3-Bromo-phenyl)- 1,3-dihydro-indol-2-one

[0370]

[0371] To the suspension of 4-(3-bromo-phenyl)-1H-indole (1.48 g, 5.44mmol) in t-BuOH—ethanol—aceticacid (3:2:1) (66 mL) was added pyridiniumtribromide (90% purity from Aldrich, 5.80 g, 16.3 mmol)) portionwise.The mixture was stirred at 27° C. for 3 hours, and then to the mixturewas added acetic acid (26 mL). Zinc dust was added to the reactionmixture portionwise until the color changed from deep red to lightyellow, and the reaction mixture was stirred at room temperature for onehour. The unreacted zinc dust was filtered off and washed with ethanol.The filtrate was concentrated, and the syrupy residue was dissolved inethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO₃ andbrine, and dried over Na₂SO₄. After filtration and evaporation, thecrude product was triturated with diethyl ether to provide product4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (1.02 g, 65%) as a tan solid.

[0372]¹H-NMR (400 MHz, DMSO-d₆) δ 10.50 (br s, 1H, NH), 7.74 (m, 1H,aromatic), 7.58 (m, 2H, aromatic), 7.41(t, 1H, aromatic), 7.28 (t, 1H,aromatic), 7.02 (d, 1H, aromatic), 6.85 (d, 1H, aromatic), 3.62 (s, 2H,CH₂).

Example A-37 4-(4-Methoxy-phenyl)-1,3-dihydro-indol-2-one

[0373]

[0374] To the suspension of4-(4-methoxy-phenyl)-1H-indole (1.84 g, 8.24mmol) in t-BuOH—ethanol—aceticacid (3:2:1) (99 mL) was added pyridiniumtribromide (90% purity from Aldrich, 8.78 g, 24.72 mmol)) portionwise.The mixture was stirred at 27° C. for 3 hours, and then to the mixturewas added acetic acid (40 mL). Zinc dust was added to the reactionmixture portionwise until the color changed from deep red to lightyellow, and the reaction mixture was stirred at room temperature for onehour. The unreacted zinc dust was filtered off and washed with ethanol.The filtrate was concentrated, and the syrupy residue was dissolved inethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO₃ andbrine, and dried over Na₂SO₄. After filtration and evaporation, thecrude product was triturated with diethyl ether to provide product4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (1.66 g, 84%) as a tansolid.

[0375]¹H-NMR (400 MHz, DMSO-d₆) δ 10.44 (br s, 1H, NH), 7.50 (m, 2H,aromatic), 7.24 (m, 1H, aromatic), 6.97 (m, 3H, aromatic), 6.78 (m, 1H,aromatic), 3.79 (s, 3H, CH₃), 3.58 (s, 2H, CH₂).

Example A-38 4-(3-Methoxy-phenyl)-1,3-dihydro-indol-2-one

[0376]

[0377] To the suspension of 4-(4-methoxy-phenyl)-1H-indole (1.73 g, 7.75mmol) in t-BuOH—ethanol—aceticacid (3:2:1) (93 mL) was added pyridiniumtribromide (90% purity from Aldrich, 8.26 g, 23.24 mmol)) portionwise.The mixture was stirred at 27° C. for 3 hours, and then to the mixturewas added acetic acid (38 mL). Zinc dust was added to the reactionmixture portionwise until the color changed from deep red to lightyellow, and the reaction mixture was stirred at room temperature for onehour. The unreacted zinc dust was filtered off and washed with ethanol.The filtrate was concentrated, and the syrupy residue was dissolved inethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO₃ andbrine, and dried over Na₂SO₄. After filtration and evaporation, thecrude product was triturated with diethyl ether to provide product4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.97 g, 52%) as a tansolid.

[0378]¹H-NMR (400 MHz, DMSO-d₆) δ 10.45 (br s, 1H, NH), 7.34 (t, 1H,aromatic), 7.25 (t, 1H, aromatic), 7.12 (d, 1H, aromatic), 7.08 (m, 1H,aromatic), 7.02 (d, 1H, aromatic), 6.93 (m, 1H, aromatic), 6.82 (d, 1H,aromatic), 3.80 (s, 3H, CH₃).

Example A-39 4-(2-Fluoro-phenyl)-1,3-dihydro-indol-2-one

[0379]

[0380] To the suspension of 4-(2-fluoro-phenyl)-1H-indole (1.30 g, 6.15mmol) in t-BuOH—ethanol—aceticacid (3:2:1) (74 mL) was added pyridiniumtribromide (5.90 g, 18.46 mmol)) portionwise. The mixture was stirred at27° C. for 3 hours, and then to the mixture was added acetic acid (30mL). Zinc dust was added to the reaction mixture portionwise until thecolor changed from deep red to light yellow, and the reaction mixturewas stirred at room temperature for one hour. The unreacted zinc dustwas filtered off and washed with ethanol. The filtrate was concentrated,and the syrupy residue was dissolved in ethyl acetate, which was washedwith water, 0.5 N HCl, sat. NaHCO₃ and brine, and dried over Na₂SO₄.After filtration and evaporation, the crude product was triturated withdiethyl ether to provide product4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (0.59 g, 42%) as a tansolid.

[0381]¹H-NMR (400 MHz, DMSO-d₆) δ 10.51 (br s, 1H, NH), 7.50 (m, 1H,aromatic), 7.48 (m, 1H, aromatic), 7.29 (m, 3H, aromatic), 6.95 (d, 1H,aromatic), 6.87 (d, 1H, aromatic), 3.39 (s, 2H, CH₂).

Example A40 4-(3-Trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one

[0382]

[0383] To the suspension of 4-(3-trifluoromethyl-phenyl)-1H-indole (3.37g, 12.90 mmol) in t-BuOH—ethanol—acetic acid (3:2:1) (155 mL) was addedpyridinium tribromide (12.38 g, 38.70 mmol)) portionwise. The mixturewas stirred at 27° C. for 3 hours, and then to the mixture was addedacetic acid (63 mL). Zinc dust was added to the reaction mixtureportionwise until the color changed from deep red to light yellow, andthe reaction mixture was stirred at room temperature for one hour. Theunreacted zinc dust was filtered off and washed with ethanol. Thefiltrate was concentrated, and the syrupy residue was dissolved in ethylacetate, which was washed with water, 0.5 N HCl, sat. NaHCO₃ and brine,and dried over Na₂SO₄. After filtration and evaporation, the crudeproduct was triturated with diethyl ether to provide product4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (2.07 g, 58%) as atan solid.

[0384]¹H-NMR (400 MHz, DMSO-d₆) δ 10.52 (br s, 1H, NH), 7.90 (d, 1H,aromatic), 7.87 (s, 1H, aromatic), 7.74 (d, 1H, aromatic), 7.69 (t, 1H,aromatic), 7.31 (t, 1H, aromatic), 7.07 (d, 1H, aromatic), 6.88 (d, 1H,aromatic), 3.64 (s, 2H, CH₂).

Example A41 4-(3-chloro4-fluoro-phenyl)-1,3-dihydro-indol-2-one

[0385]

[0386] To the suspension of 4-(3-chloro-4-fluoro-phenyl)-1H-indole (2.03g, 8.26 mmol) in t-BuOH—ethanol—aceticacid (3:2:1) (99 mL) was addedpyridinium tribromide (7.93 g, 24.79 mmol)) portionwise. The mixture wasstirred at 27° C. for 3 hours, and then to the mixture was added aceticacid (40 mL). Zinc dust was added to the reaction mixture portionwiseuntil the color changed from deep red to light yellow, and the reactionmixture was stirred at room temperature for one hour. The unreacted zincdust was filtered off and washed with ethanol. The filtrate wasconcentrated, and the syrupy residue was dissolved in ethyl acetate,which was washed with water, 0.5 N HCl, sat. NaHCO₃ and brine, and driedover Na₂SO₄. After filtration and evaporation, the crude product wastriturated with diethyl ether to provide product4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (1.39 g, 64%) as atan solid.

[0387]¹H-NMR (400 MHz, DMSO-d₆) δ 10.52 (br s, 1H, NH), 7.79 (dd, 1H,aromatic), 7.59 (m, 1H, aromatic), 7.49 (t, 1H, aromatic), 7.28 (t, 1H,aromatic), 7.02 (d, 1H, aromatic), 6.85 (d, 1H, aromatic), 3.63 (s, 2H,CH₂).

Example A42 4-(4-Trifluoromethoxy-phenyl)-1,3-dihydroindol-2-one

[0388]

[0389] To the suspension of 4-(4-trifluoromethoxy-phenyl)-1H-indole(4.93 g, 17.78 mmol) in t-BuOH—ethanol—aceticacid (3:2:1) (261 mL) wasadded pyridinium tribromide (17.06 g, 53.34 mmol)) portionwise. Themixture was stirred at 27° C. for 3 hours, and then to the mixture wasadded acetic acid (105 mL). Zinc dust was added to the reaction mixtureportionwise until the color changed from deep red to light yellow, andthe reaction mixture was stirred at room temperature for one hour. Theunreacted zinc dust was filtered off and washed with ethanol. Thefiltrate was concentrated, and the syrupy residue was dissolved in ethylacetate, which was washed with water, 0.5 N HCl, sat. NaHCO₃ and brine,and dried over Na₂SO₄. After filtration and evaporation, the crudeproduct was triturated with diethyl ether to provide product4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (2.05 g, 39%) as atan solid.

[0390]¹H-NMR (400 MHz, DMSO-d₆) δ 10.50 (br s, 1H, NH), 7.71 (d, 2H,aromatic), 7.43 (d, 2H, aromatic), 7.29 (t, 1H, aromatic), 7.03 (d, 1H,aromatic), 6.85 (d, 1H, aromatic), 3.62 (s, 2H, CH₂).

Example A43 4-[3-(2-Hydroxy-ethyl)-phenyl]-1,3-dihydro-indol-2-one

[0391]

[0392] To a suspension of NaBH₄ (600 mg, 16 mmol) in 15% H₂0/ MeOH (6mL) under nitrogen at rt was added dropwise a solution of[3-(2-oxo-2,3-dihydro-1H-indol-4yl)-phenyl]-acetic acid methyl ester(450 mg, 1.6 mmol) in THF (3 mL). After stirring at rt for overnight, tothe reaction was added CaCl₂ (300 mg) and stirring was continued foranother 5 hours. The reaction was quenched with acetic acid (2 mL),concentrated, diluted with ethyl acetate, washed with 0.5 N HCl (3×15mL), 10% NaHCO₃ (3×15 mL), brine (1×), dried and concentrated. The oilyresidue was purified to give 384 mg (95%) of4-[3-(2-hydroxy-ethyl)-phenyl]-l,3-dihydro-indol-2one.

[0393]¹H-NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H, NH), 7.35-7.43 (m, 3H),7.28 (t, 1H), 7.23 (d, 1H), 7.03 (d, 1H), 6.83 (d, 1H), 4.68 (t, 1H,OH), 3.67 (m, 2H), 3.62 (s, 2H), 2.80 (t, 2H).

[0394] MS m/z 254.1 [M⁺+1].

Example A-44 2-Fluoro-5-(2-oxo-2,3-dihydro-1H-indol4-yl)-benzonitrile

[0395]

[0396] To the suspension of2-fluoro-5-(1H-indol-4-yl)-benzonitrile (2.68g, 11.34 mmol) in t-BuOH:ethanol:acetic acid (72 mL:43 mL:23 mL) wasadded pyridinium tribromide (10.91 g, 34.1 mmol) portionwise. Themixture was stirred at room temperature for 3 hours, and then to themixture was added acetic acid (55 mL). Zinc dust (4 g, 61.2 mmol) wasadded to the reaction mixture portionwise. After stirring for one hour,any unreacted zinc was filtered off and most of the solvent was removedunder reduced pressure. The residue was diluted with ethyl acetate,washed with water (3×), sat. NaHCO₃, brine, dried over Na₂SO₄,concentrated and triturated with ether to give 1.93 g (68%) of2-fluoro-5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzonitrile.

[0397]¹H-NMR (400 MHz, DMSO-d₆) δ 10.52 (s, 1H, NH), 8.13 (dd, 1H), 7.96(m, 1H), 7.59 (t, 1H), 7.28 (t, 1H), 7.03 (d, 1H), 6.85 (d, 1H), 3.64(s, 2H).

[0398] MS m/z 251.4 [M−1].

Example A45 4-Biphenyl-3-yl-1,3-dihydro-indol-2-one

[0399]

[0400] To the suspension of 4-bipheny-3-yl-1H-indole (3.5 g, 13 mmol) int-BuOH: ethanol:acetic acid (82 mL:49 mL:269 mL) was added pyrdiniumtribromide (12.7 g, 40 mmol) portionwise. The mixture was stirred atroom temperature for 3 hours, and then to the mixture was added aceticacid (63 mL). Zinc dust (4.39 g, 67 mmol) was added to the reactionmixture portionwise. After stirring for one hour, any unreacted zinc wasfiltered off and most of the solvent was removed under reduced pressure.The residue was diluted with ethyl acetate, washed with water (3×), sat.NaHCO₃, brine, dried over Na₂SO₄, concentrated and triturated with etherto give 2.67 g (72%) of 4-biphenyl-3-yl- 1,3 -dihydro-indol-2-one.

[0401]¹H-NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H, NH), 7.78 (m, 1H), 7.71(m, 2H), 7.65 (m, 1H), 7.53 (m, 2H), 7.47 (m, 2H), 7.37 (m, 1H), 7.28(t, 1H), 7.10 (d, 1H), 6.83 (d, 1H), 3.66 (s, 2H).

[0402] MS m/z 286 [M⁺+1].

Example A-46 4-Biphenyl-2-yl-1,3-dihydro-indol-2-one

[0403]

[0404] To the suspension of 4-bipheny-2-yl-1H-indole (1.18 g, 4.4 mmol)in t-BuOH:ethanol:acetic acid (28 mL:17 mL:9 mL) was added pyridiniumtribromide (4.39 g, 13.7 mmol) portionwise. The mixture was stirred atroom temperature for 3 hours, and then to the mixture was added aceticacid (22 mL). Zinc dust (1.63 g, 25 mmol) was added to the reactionmixture portionwise. After stirring for one hour, any unreacted zinc wasfiltered off and most of the solvent was removed under reduced pressure.The residue was diluted with ethyl acetate, washed with water (3×), sat.NaHCO₃, brine, dried over Na₂SO₄, concentrated and triturated with etherto give 0.93 g (74%) of 4-biphenyl-2-yl-1,3 -dihydro-indol-2-one.

[0405]¹H-NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H, NH), 7.35-7.45 (m, 4H),7.2 (m, 4H), 7.12 (m, 1H), 7.08 (t, 1H), 6.67 (m, 2H), 2.86 (s, 2H).

Example A-47 4-(3,5-Difluoro-phenyl)-1,3-dihydro-indol-2-one

[0406]

[0407] To the suspension of4-(3,5-difluoro-phenyl)-1H-indole (13.52 g,59 mmol) in t-BuOH:ethanol:acetic acid (375 mL:225 mL:115 mL) was addedpyridinium tribromide (57 g, 177 mmol) portionwise. The mixture wasstirred at room temperature for 3 hours, and then to the mixture wasadded with acetic acid (286 mL). Zinc dust (19.25 g, 295 mmol) was addedto the reaction mixture portionwise. After stirring for one hour, anyunreacted zinc was filtered off and most of the solvent was removedunder reduced pressure. The residue was diluted with ethyl acetate,washed with water (5×), neutralized with 1N HCl, washed with sat.NaHCO₃, brine, dried over Na₂SO₄, concentrated and triturated with etherto give 9.88 g (68%) of 4-(3,5-difluoro-phenyl)-1,3-dihydro-indol-2-one.

[0408]¹H-NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H, NH), 7.2-7.35 (m, 5H),7.04 (dd, 1H), 6.86 (d, 1H), 3.66 (s, 2H).

[0409] MS m/z 244 [M−1].

Example A-48 [3-(2-Oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetic acid

[0410]

[0411] To the suspension of [3-(1H-indol-4-yl)-phenyl]-acetic acid (3.52g, 14 mmol) in t-BuOH:ethanol:acetic acid (93 mL:56 mL:67 mL) was addedpyridinium tribromide (14.14 g, 42 mmol) portionwise. The mixture wasstirred at room temperature for 3 hours, and then to the mixture wasadded acetic acid (60 mL). Water (2 mL) and zinc dust (14 g, excess)were added to the reaction mixture portionwise. After stirring for onehour, any unreacted zinc was filtered off and most of the solvent wasremoved under reduced pressure. The residue was diluted with ethylacetate, washed with water (3×), sat. NaHCO₃, brine, dried over Na₂SO₄and concentrated to give 2.59 g (70%) of[3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetic acid.

[0412]¹H-NMR (400 MHz, DMSO-d₆) δ 12.32 (br s, 1H, OH), 10.46 (s, 1H,NH), 7.43 (m, 2H), 7.37 (t, 1H), 7.25 (m, 2H), 6.98 (dd, 1H), 6.80 (d,1H), 3.63 (s, 2H), 3.58 (s, 2H).

[0413] MS m/z 266 [M−1].

Example A-49N,N-Dimethyl-2-[3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetamide

[0414]

[0415] To the suspension of2-[3-(1H-iIndol-4-yl)-phenyl]-N,N-dimethyl-acetamide (1.6 g, 5 mmol) int-BuOH:ethanol:acetic acid (332 mL:20 mL:24 mL) was added pyridiniumtribromide (5 g, 15 mmol) portionwise. The mixture was stirred at roomtemperature for 3 hours, and then to the mixture was added acetic acid(22 mL). Water (0.7 mL) and zinc dust (5 g) were added to the reactionmixture portionwise. After stirring for one hour, any unreacted zinc wasfiltered off and most of the solvent was removed under reduced pressure.The residue was diluted with ethyl acetate, washed with 0.5 N HCl (2×),10% Na₂CO₃ (2×), brine (2×), water, dried over Na₂SO₄, concentrated andtriturated with ether to giveN,N-dimethyl-2-[3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetamide.

[0416] MS m/z 293 [M−1].

Example A-504-[3-(2-Dimethylamino-ethyl)-phenyl]-1,3-dihydro-indol-2-one

[0417]

[0418] To the suspension of{2-[3-(1H-indol-4-yl)-phenyl]-ethyl}-dimethyl-amine (600 mg, 2.2 mmol)in t-BuOH:ethanol:acetic acid (14.5 mL:8.8 mL:10.5 mL) was addedpyridinium tribromide (2.3 g, 6.6 mmol) portionwise. The mixture wasstirred at room temperature for 3 hours, and then to the mixture wasadded acetic acid (9.24 mL). Water (0.32 mL) and zinc dust (2.2 g, 61.2mmol) was added to the reaction mixture portionwise. After stirring forone hour, any unreacted zinc was filtered off and most of the solventwas removed under reduced pressure. The residue was diluted with ethylacetate, washed with water (3×), sat. NaHCO₃, brine, dried over Na₂SO₄and concentrated. The residue was dissolved in methanol (10 mL) andhydrogenated using 10% Pd- C for overnight. The reaction was filteredthrough celite and the filtrate was concentrated. The residue waspurified on a silica gel column to give4-[3-(2-dimethylamino-ethyl)-phenyl]- 1,3-dihydro-indol-2-one

[0419]¹H-NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H, NH), 7.37-7.46 (m, 3H),7.26 (t, 2H), 6.81 (d, 1H), 3.60 (s, 2H), 3.08 (m, 2H), 2.93 (m, 2H),2.62 (s, 6H, 2×CH₃).

[0420] MS m/z 281.1 [M⁺+1].

Example A-51 4-(3-Amino-1H-indazol-5-yl)-1,3-dihydro-indol-2-one

[0421]

[0422] To the suspension of5-(1H-indol-4-yl)-1H-indazol-3-ylamine (0.82g, 3.33 mmol) in t-BuOH:ethanol:acetic acid (20.5 mL:12 mL:6 mL) wasadded pyridinium tribromide (3.17 g, 9.9 mmol) portionwise. The mixturewas stirred at room temperature for 3 hours, it immediately became adark pink color. Zinc dust (excess) was added to the reaction mixtureportionwise. After stirring for one hour, the unreacted zinc wasfiltered off and the solvent was removed under reduced pressure. Theresidue was washed with ample of water. The solid was triturated withDCM to give 0.563 g (77%) of4-(3-amino-1H-indazol-5-yl)-1,3-dihydro-indol-2-one.

Example A-52 4-(2,6-Difluoro-phenyl)-1,3-dihydro-indol-2-one

[0423]

[0424] To the suspension of4-(2,6-difluoro-phenyl)-1H-indole (9.5 g,41.4 mmol) in t-BuOH:ethanol:acetic acid (262 mL:155 mL:81 mL) was addedpyridinium tribromide (40.28 g, 126 mmol) portionwise. The mixture wasstirred at room temperature for 3 hours, and then to the mixture wasadded more acetic acid (200 mL). Zinc dust (14.2 g, 217 mmol) was addedto the reaction mixture portionwise. After stirring for one hour, theunreacted zinc was filtered off and most of the solvent was removedunder reduced pressure. The residue was diluted with ethyl acetate,washed with water (5×), sat. NaHCO₃ (2×), brine (3×), dried over Na₂SO₄,concentrated, triturated with ether to give 7.1 g (70%) of4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one as a white solid.

[0425]¹H-NMR (400 MHz, DMSO-d₆) δ 10.53 (s, 1H, NH), 7.50 (m, 1H), 7.25(m, 3H), 6.90 (m, 2H), 3.25 (s, 2H).

Example A-53 3-(2-oxo-2,3-dihydro-1H-indol4-yl)-benzoic acid

[0426]

[0427] To the suspension of 3-(1H-iIndol-4-yl)-benzoic acid (7.58 g, 33mmol) in t-BuOH:ethanol:acetic acid (150mL:100mL:50 mL) was addedpyridinium tribromide (31.66 g, 99 mmol) portionwise. The mixture wasstirred at room temperature for 2 hours, and then to the mixture wasadded with acetic acid (150 mL). Water (4 mL) and Zinc dust (13.07 g,200 mmol) was added to the reaction mixture portionwise and stirring wascontinued at room temperature for 2 hours. The solvent was removed underreduced pressure. The oily residue was suspended in 1N HCl (400 mL) andstirred at room temperature overnight. The precipitate solid wascollected by filtration, purified by recrystallization from ethylacetate to give (6.4 g, 77%) of3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzoic acid as a pinkish whitesolid.

[0428]¹H-NMR (400 MHz, DMSO-d₆) δ 10.50 (br s, 1H, NH), 8.01-8.05 (m,1H), 7.90-7.95 (m, 1H), 7.82-7.87 (m, 1H), 7.54-7.60 (m, 1H), 7.26-7.32(m, 1H), 7.04 (d, J=7.1 Hz, 1H), 6.84 (d, J=7.4 Hz, 1H), 3.58 (s, 2H).

Example A-54 N-Methyl-3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzamide

[0429]

[0430] A mixture of 3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzoic acid(1.27 g, 5.0 mmol), HOBt (0.68 g, 5.0 mmol) and EDC (1.44 g, 7.5 mmol)in DMF (10 mL) was stirred at room temperature for 30 minutes. To themixture was added methylamine (2M in THF, 3.75 mL, 7.5 mmol), it wasthen stirred at room temperature for overnight. Most of the solvent wasremoved under reduced pressure and the residue was diluted with sat.NaHCO₃ (20 mL). The precipitate was collected by filtration, washed withwater and dried. The crude product was recrystallized from DCM-hexane togive 1.14 g (86%) ofN-methyl-3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzamide as a light yellowsolid.

[0431]¹H-NMR (400 MHz, DMSO-d₆) δ 8.46-8.53 (m, 1H), 7.94 (m, 1H),7.80-7.85 (m, 1H), 7.68-7.74 (m, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.28 (t,J=7.8 Hz, 1H), 7.05 (dd, J=0.8, 7.8 Hz, 1H), 6.83 (d, J=7.4 Hz, 1H),3.63 (s, 2H), 2.79 (d, J =4.6 Hz, 3H).

[0432] MS m/z 267 [M⁺+1].

Example A-55 4-(3,4-Dimethoxy-phenyl)-1,3-dihydro-indol-2-one

[0433]

[0434] To the suspension of 4-(3,4-dimethoxy-phenyl)-1H-indole (14.7 g,58 mmol) in t-BuOH:ethanol:acetic acid (367 mL:217 mL:113 mL) was addedpyridinium tribromide (55.68 g, 174 mmol) portionwise. The mixture wasstirred at room temperature for 3 hours, and then to the mixture wasadded more acetic acid (287 mL). Zinc dust (18.95 g, 290 mmol) was addedto the reaction mixture portionwise. After stirring for one hour, waterwas added to the reaction. The unreacted zinc was filtered off and mostof the solvent was removed under reduced pressure. The residue wasdiluted with ethyl acetate, washed with water (6×), sat. NaHCO₃ (2×),brine (3×), dried over Na₂SO₄, concentrated and triturated with ether togive 10.14 g (65%) of 4-(3,4-dimethoxy-phenyl)-1,3-dihydro-indol-2-oneas an earth colored solid.

[0435]¹H-NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H, NH), 7.22 (t, 1H), 7.18(m, 2H), 7.0 (m, 2H), 6.77 (d, 1H), 3.79 (s, 3H, OCH₃), 3.77 (s, 3H,OCH₃), 3.6 (s, 2H).

Example A-56 4-[3-(2-Hydroxy-ethoxy)-phenyl]-1,3-dihydro-indol-2-one

[0436]

[0437] To the suspension of 2-[3-(1H-indol-4-yl)-phenoxy]-ethanol (5.4g, 21 mmol) in t-BuOH:ethanol:acetic acid (139.5 mL:84 mL:100.5 mL) wasadded pyridinium tribromide (21.21 g, 63 mmol) portionwise. The mixturewas stirred at room temperature for 3 hours, and then to the mixture wasadded more acetic acid (90 mL) and water (3 mL). Zinc dust (21 g) wasadded to the reaction mixture portionwise. After stirring for one hour,the unreacted zinc was filtered off and most of the solvent was removedunder reduced pressure. The residue was diluted with ethyl acetate,washed with IN HCl (3×), water (1×), brine (2×), dried over Na₂SO₄,concentrated. The residue was recrystallized to give 1.82 g (32%) of4-[3-(2-hydroxy-ethoxy)-phenyl]-1,3-dihydro-indol-2-one.

[0438]¹H-NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H, NH), 7.33 (t, 1H), 7.25(t, 1H), 7.09 (d, 1H), 7.06 (m, 1H), 7.0 (dd, 1H), 6.92 (dd, 1H), 6.80(d, 1H), 4.86 (t, 1H), 4.02 (t, 2H), 3.71 (q, 2H), 3.58 (s, 2H). [03521MS m/z 270 [M++1].

Example A-57 4-(2,3-Difluorophenyl)-1,3-dihydro-indol-2-one

[0439]

[0440] To the suspension of 4-(2,3-difluoro-phenyl)-1H-indole (2.85 g,12.4 mmol) in t-BuOH:ethanol:acetic acid (78.5 mL:46.5 mL:24.13 mL) wasadded pyridinium tribromide (11.93 g, 37.3 mmol) portionwise. Themixture was stirred at room temperature for 3 hours, and then to themixture was added with acetic acid (60 mL). Zinc dust (4.1 g, 62.2 mmol)was added to the reaction mixture portionwise. After stirring for onehour, any unreacted zinc was filtered off and most of the solvent wasremoved under reduced pressure. The residue was diluted with ethylacetate, washed with water (5×), sat NaHCO₃, brine, dried over Na₂SO₄,concentrated and triturated with ether to give 2.32 g (76%) of4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one as an earth coloredsolid.

[0441]¹H-NMR (400 MHz, DMSO-d₆) δ 10.53 (br s, 1H, NH), 7.45 (m, 1H),7.29 (m, 3H), 6.96 (d, J=7.8 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 3.41 (s,2H).

[0442] MS m/z 246.2 [M⁺+1].

Example A-58 4-Bromo-5-methoxy-1,3-dihydro-indol-2-one

[0443]

[0444] To the suspension of 5-methoxyindole (5.0 g, 34 mmol) int-BuOH:ethanol:acetic acid (215 mL:127 mL:66 mL) was added pyridiniumtribromide (32.6 g, 102 mmol) portionwise. The mixture was stirred atroom temperature for 3 hours, and then to the mixture was added withmore acetic acid (165 mL). Zinc dust (11.1 g, 170 mmol) was added to thereaction mixture portionwise. After stirring for one hour, the unreactedzinc was filtered off, and the solvent was removed under reducedpressure. The residue was diluted with water, extracted with ethylacetate. The combined extracts were washed with water (5×), sat. NaHCO₃(2×), brine (3×), dried over Na₂SO₄, concentrated, triturated with etherto give 2.12 g (26%) of 4-bromo-5-methoxy- 1,3-dihydro-indol-2-one.

[0445]¹H-NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H, NH), 6.90 (d, J=8 Hz,1H), 6.74 (d, J =8 Hz, I1H), 3.77 (s, 3H, OCH₃), 3.42 (s, 2H).

Example A-59 4-(2,4-Difluoro-phenyl)-1,3-dihydro-indol-2-one

[0446]

[0447] To the suspension of 4-(2,4-difluoro-phenyl)-1H-indole (6.42 g,28 mmol) in t-BuOH:ethanol:acetic acid (177 mL:105 mL:55 mL) was addedpyridinium tribromide (27 g, 84 mmol) portionwise. The mixture wasstirred at room temperature for 3 hours, and then to the mixture wasadded with acetic acid (136 mL). Zinc dust (9.8 g, 150 mmol) was addedto the reaction mixture portionwise. After stirring for one hour, anyunreacted zinc was filtered off and most of the solvent was removedunder reduced pressure. The residue was diluted with ethyl acetate,washed with water (5×), neutralized with IN HCl, washed with sat.NaHCO₃, brine, dried over Na₂SO₄, concentrated and triturated with etherto give 5.16 g (75%) of 4-(2,4-difluoro-phenyl)-1,3-dihydro-indol-2-one.

[0448]¹H-NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H, NH), 7.54 (m, 1H), 7.35(m, 1H), 7.25 (t, 1H), 7.16 (m, 1H), 6.91 (d, 1H), 6.85 (d, 1H), 3.37(s, 2H).

Example A-60 4-(2-Chloro-phenyl)-1,3-dihydro-indol-2-one

[0449]

[0450] To the suspension of 4-(2-chloro-phenyl)-1H-indole (2.4 g, 10.6mmol) in t-BuOH:ethanol:acetic acid (67 mL:40 mL:21 mL) was addedpyridinium tribromide (10.5 g, 32 mmol) portionwise. The mixture wasstirred at room temperature for 3 hours, and then to the mixture wasadded acetic acid (52 mL). Zinc dust (3.5 g, 53 mmol) was added to thereaction mixture portionwise. After stirring for one hour, any unreactedzinc was filtered off and most of the solvent was removed under reducedpressure. The residue was diluted with ethyl acetate, washed with water(3×), sat. NaHCO₃, brine, dried over Na₂SO₄, concentrated and trituratedwith ether to give 1.96 g (76%) of4-(2-chloro-phenyl)-1,3-dihydro-indol-2-one.

[0451]¹H-NMR (400 MHz, DMSO-d₆) δ 10.53 (s, 1H, NH), 7.56 (m, 1H), 7.41(m, 3H) 7.26 (t, 1H), 6.86 (m, 2H), 3.26 (s, 2H).

[0452] MS m/z 244.2 [M⁺+1].

Example A-61 [3-(2-Oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetic acidmethyl ester

[0453]

[0454] To the suspension of [3-(1H-indol-4-yl)-phenyl]-acetic acidmethyl ester (3.72 g, 14 mmol) in t-BuOH:ethanol:acetic acid (93 mL:56mL:67.2 mL) was added pyridinium tribromide (14.14 g, 44 mmol)portionwise. The mixture was stirred at room temperature for 3 hours,and then to the mixture was added acetic acid (60 mL). Water (2 mL) andzinc dust (14 g, excess) was added to the reaction mixture portionwise.After stirring at rt for one hour, any unreacted zinc was filtered offand most of the solvent was removed under reduced pressure. The residuewas diluted with diluted with water (380 mL), extracted with ethylacetate, washed with 0.5 N HCl (2×), 10% Na₂CO₃, (2×), brine (2×), water(1×), dried over Na₂SO₄, concentrated and triturated with ether to give[3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetic acid methyl ester.

[0455] MS m/z 282 [M⁺+1].

Syntheses of the Precursor, Pyrrole Aldehydes:5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (Pyrrole Aldehyde-1)

[0456]

[0457] Step 1:

[0458] t-Butyl-3-oxobutyrate (158 g, 1 mol) was dissolved in 200 mL ofacetic acid in a 500 mL 3-neck round bottom flask equipped with athermometer, addition funnel and mechanical stirring. The mixture wascooled in an ice bath to about 10 ° C. Sodium nitrite (69 g, 1 mol) wasadded over 75 minutes keeping the temperature under 15 ° C. The coldbath was removed and the mixture stirred for 30 minutes and then allowedto stand for 3.5 hours to give t-butyl-2-hydroximino-3-oxobutyrate.

[0459] Ethyl-3-oxobutyrate (130 g, 1 mol) was dissolved in 400 mL ofacetic acid in a 2 L 3-neck round bottom flask equipped with athermometer, an addition funnel, mechanical stirring and placed in anoil bath. Zinc dust (50 g, 0.76 mol) was added and the mixture heated to60 ° C. with stirring. The crude t-butyl-2-hydroximino-3-oxobutyratesolution prepared above was cautiously added keeping the temperature atabout 65 ° C. by slowing the addition and cooling the flask. More zincdust (4×50 g, 3.06 mol) was added in portions during the addition withthe last portion added after all the t-butyl ester had been added. Thetemperature of the mixture reached a maximum of 80 ° C. At the end ofthe additions the temperature was 64 ° C. The temperature was increasedby heating to 70-75 ° C. for one hour and then poured into 5 L of water.The gray floating precipitate was collected by vacuum filtration andwashed with 2 L of water to give 354 g of wet crude product. The crudeproduct was dissolved in 1 L of hot methanol and hot filtered to removezinc. The filtrate was cooled to give a precipitate that was collectedby vacuum filtration to give 118 g of product. The filtrate was put inthe refrigerator overnight to give a total of 173.2 g of3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethylester.

[0460] Step 2:

[0461] 3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester4-ethyl ester (80.1 g, 0.3 mol) and 400 mL of trifluoroacetic acid werestirred for 5 minutes in a 2 L 3-neck round bottom flask equipped withmechanical stirring and warmed to 40° C. in an oil bath. The mixture wasthen cooled to −5 ° C. and triethyl orthoformate (67.0 g, 0.45 mol) wasadded all at once. The temperature increased to 15 ° C. The mixture wasstirred for about 1 minute, removed from the cold bath and then stirredfor 1 hour. The trifluoroacetic acid was removed by rotary evaporationand the residue put in the refrigerator where it solidified. The solidwas dissolved by warming and poured into 500 g of ice. The mixture wasextracted with 800 mL of dichloromethane to give a red solution and abrown precipitate, both of which were saved. The precipitate wasisolated and washed with 150 mL of saturated sodium bicarbonatesolution. The dichloromethane phase was washed with 150 mL of sodiumbicarbonate and both bicarbonate solutions discarded. Thedichloromethane solution was washed with 3 times with 100 mL of watereach time. The dichloromethane solution was evaporated to dryness andthe dark residue recrystallized twice from hot ethyl acetate afterdecolorizing with Darco to give golden yellow needles. The brownprecipitate was recrystallized from 350 mL of hot ethyl acetate afterdecolorizing with Darco to give a yellow-red solid. All therecrystallized solids were combined and recrystallized from 500 mL ofhot ethanol to give 37.4 g (63.9 %) of5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester as yellowneedles (mp 165.6 -166.3 ° C, lit. 163 -164 ° C). The evaporatedresidues from the ethyl acetate and ethanol mother liquors wererecrystallized from 500 mL of ethanol to give 10.1 g (17.1 %) of asecond crop of dirty yellow needles.

[0462] Step 3:

[0463] 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture wasrefluxed for 3 hours, cooled to room temperature and acidified with 6 Nhydrochloric acid to pH3. The solid was collected by filtration, washedwith water and dried in a vacuum oven overnight to give 1.6 g (93%) of5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. 103691 ¹H NMR (300MHz, DMSO-d₆) 5 12.09 (s, br, 2H, NH & COOH), 9.59 (s, 1H, CHO), 2.44(s, 3H, CH₃), 2.40 (s, 3H, CH₃).

[0464] MS m/z 167 (M+).

[0465] II. General amidation procedure:

[0466] The 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid isdissolved in DMF (0.3M) with stirring. To the solution is addedI-ethyl-3-(3-dimethylamino-propylcarbodiimide hydrochloride (EDC, 1.2equiv.), 1-hydroxybenzotriazole (HOBt, 1.2 eq) followed by theappropriate amine (1.2 eq). The reaction solution is stirred for 12h,and then DMF solvent was removed. The residue was purified on a silicagel column eluting with 1-5% methanol in dichloromethane to provide theproduct.

Example B-13,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde

[0467]

[0468] 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (5 g, 29.9mmol) reacted with N-methylpiperazine (4.0 mL) to give 5.3g (72%) of3,5-imethyl-4-(4-piperazine- 1 -carbonyl)- 1 H-pyrrole-2-carbaldehyde.

[0469]¹H NMR (360 MHz, DMSO-d₆) δ 11.82 (s, 1H, NH), 9.50 (s, 1H, CHO),3,14 (br m, 4H, 2×CH₂), 2.29 (br m, 4H, 2×CH₂), 2.19 (s, 3H, CH₃), 2.17(s, 3H, CH₃), 2.14 (s, 3H, CH₃).

[0470] MS m/z 249 [M]⁺.

Example B-2 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide

[0471]

[0472] 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (5 g, 2.99mmol) reacted with N,N-diethylethylenediamine (4.62 mL) to give 6.19g(78%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylarnino-ethyl)-amide.

[0473]¹H NMR (360 MHz, DMSO-d₆ )δ 11.7 (br s, H, NH), 9.52 (s,1H, CHO),7.27 (m,1H, CONH), 3.2 (m, 2H, NCH₂), 2.5 (m, 6H, 3×NCH₂), 2.35 (s, 3H,CH₃), 2.30 (s, 3H, CH₃), 0.95 (t, J=6.7 Hz, 6H, 2×NCH₂CH₃).

[0474] MS m/z 266 (M⁺+1)

Example B-3 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-pyrrolidin-1 -yl-ethyl)-amide

[0475]

[0476] 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (5 g, 29.9mmol) reacted with 1-(2-aminoethyl)pyrrolidine (4.1 g, 35.9 mmol) togive 5.7 g (73%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide.

[0477]¹H NMR (360 MHz, DMSO-d₆) δ 11.79 (br s, 1H, NH), 9.53 (s, 1H,CHO), 1H, CONH), 3.28-3.34 (m, 2H, NCH₂), 2.53-2.60 (m, 6H, NCH₂ andCH₂), 2.35 (s, 3H, CH₃), 2.3 (s, 3H, CH₃), 1.68 (m, 4H, 2×CH₂).

[0478] MS m/z 264.1 (M⁺)

Example B-4 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-[1,2,31triazol-1-yl-ethyl)-amide

[0479]

[0480]5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2 g, 11.96mmol) reacted with 2-[1,2,3]triazol-1-yl-ethylamine (2.66 g, 14.36 mmol)to give 3.05 g (98%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol- 1-yl-ethyl)-amide.

[0481]¹H NMR (360 MHz, DMSO-d₆) δ 11.83 (br s, 1H, NH), 9.52 (s, 1H,CHO), 8.12 (d, 1H, J=1.3 Hz, triazole hydrogen), 7.72 (d, 1H, J=1.27 Hz,triazole hydrogen), 7.63 (t, 1H, J=5.6 Hz, CONH), 4.55 (m, 2H, NCH₂),3.66 (m, 2H, CH₂), 2.26 (s, 3H, CH₃), 2.21 (s, 3H, CH₃).

[0482] MS m/z 262 (M⁺+1).

Example B-53,5-Dimethyl-4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-1H-pyrrole-2-carbaldehyde

[0483]

[0484] 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2 g,11.96mmol) reacted with cis-2,6-dimethylpiperazine (2.66 g, 14.36 mmol) togive 2.27g (72%) of 3,5-dimethyl-4-[(cis)-3,5-dimethyl-piperazine-I1-carbonyl]- 1H-pyrrole-2-carbaldehyde.

[0485]¹HNMR (360 MHz, DMSO-d₆)δ 11.84 (br s, 1H, NH), 9.51 (s,1H, CHO),4.30 (br s 1H, NE), 2.50 (m, 4H, 2×CH₂), 2.28 (m, 8H, 2×CH₃ and 2×CH),0.96 (m, 6H, 2×CH₃).

[0486] MS m/z 264 (M⁺+1).

Example B-6 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(3-diethylamino-propyl)-amide

[0487]

[0488] 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3.0 g, 17.9mmol) reacted with diethylamino propylamine (2.57 g, 19.7 mmol) to give3.19g (64%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(3-diethylamino-propyl)-amide.

[0489]¹H NMR (360 MHz, DMSO-d₆) δ 11.78 (br s, 1H, NH), 9.52 (s, 1H,CHO), 7.5 (m, 1H, CONH), 3.21 (q, J=6.4 Hz, 2H, NCH₂CH₃), 2.5 (m, 6H,NCH₂CH₃ and 2×NCH₂), 2.35 (s, 3H, CH₃), 2.29 (s, 3H, CH₃), 1.63 (m, 2H,CH₂), 0.96 (t, J=6.8 Hz, 6H, NCH₂CH₃).

[0490] MS m/z 280 (M⁺+1).

Example B-7 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diisopropylamino-ethyl)-amide

[0491]

[0492] 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3.0 g, 17.9mmol) reacted with dilsopropylamino ethylamine (3.56 mL, 19.7 mmol) togive 4.93g (94%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(3-diisopropylamino-ethyl)-amide.

[0493]¹H NMR (360 MHz, DMSO-d₆) δ 11.78 (br s, 1H, NH), 9.54 (s, 1H,CHO), 7.29 (m, 1H, CONH), 3.15 (m, 2H, CH₂), 2.51 (m, 4H, CH₂ and 2×CH),2.38 (s, 3H, CH₃), 2.32 (s, 3H, CH₃), 0.97 (d, 12H, 4×CH₃).

[0494] MS m/z 294 (M⁺+1).

Example B-8 5-Formyl-4-methyl-1H-pyrrole-3-carboxylic acid

[0495]

[0496] Step 1: Preparation of 4-Methyl-1H-pyrrole-3-carboxylic acidethyl ester

[0497] To a suspension of sodium hydride (4 g of 60% dispersion, 2eq,washed with diethyl ether) in diethyl ether (200 mL), cooled in an icebath with stirring was added slowly a solution of ethyl crotonate (6.2mL, 50 mmol) and p-tosylmethyl isocyanide (9.7 g, 50 mmol) in 80 mL ofDMSO and 160 mL diethyl ether. Upon complete addition of the solution,the reaction mixture was stirred at room temperature for 1 hr. Thereaction was quenched with 400 mL water and extracted into diethyl ether(2×100 mL), dried (MgSO₄) and concentrated to afford 6g (78%) of4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester as a brown oil whichsolidified upon standing.

[0498]¹H NMR (300 MHz, DMSO-d₆) δ 11.1 (br s, 1H, NH), 9.78 (t, J=2.7Hz, 1H), 6.56 (s, 1H), 4.12 (q, J=7.2 Hz, 2H, OCH₂CH₃), 2.15 (s, 3H,CH₃), 1.22 (t, J=7.2 Hz, 3H, OCH₂CH₃).

[0499] MS m/z 153 [M⁺].

[0500] (Lit. ref.: Cheng et al., J. Heterocyclic Chem., 1976, 13,1145-1147).

[0501] Step 2: Preparation of 5-Formyl-4-methyl-1H-pyrrole-3-carboxylicacid ethyl ester

[0502] POCl₃ (4 mL, 1.1 eq) added to 9 mL (3 eq) of DMF cooled in an icebath. After 15 mins, a solution of the 4-methyl-1H-pyrrole-3-carboxylicacid ethyl ester (6 g, 39.2 mmol) in DMF (2M, 20 mL) was added to thereaction and stirring continued at rt. After 2 hr, the reaction mixturewas diluted with water (100 mL) and basified to pH=1 1 with IN NaOH. Theaqueous layer was extracted into DCM (2×250 mL), washing the combinedorganic layers with water (2×400 mL), dried (MgSO₄), filtered through aplug of silica and concentrated to afford a pinkish solid. Triturationwith hexanes afforded 3.3g (46%) of5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester as a tansolid

[0503]¹H NMR (300 MHz, DMSO-d₆) δ 12.4 (br s, 1H, NH), 9.69 (s, 1H,CHO), 7.59 (s, 1H), 4.16 (q, J =6.8 Hz, 2H, OCH₂CH₃), 2.48 (s, 3H, CH₃),1.24 (t, J=6.8 Hz, 3H, OCH₂CH₃).

[0504] MS m/z 181 [M⁺].

[0505] (Lit. ref.: Bonnett, Raymond; Hamzetash, Dariush; Valles, MariaAsuncion; J. Chem. Soc. Perkin Trans 1; 1987; 1387-1388).

[0506] Step 3: Preparation of 5-formyl-4-methyl-1H-pyrrole-3-carboxylicacid

[0507] KOH (5 g, 2 eq) was added to a suspension of5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (8.13 g, 44.8mmol) in water (100 mL) and EtOH (50 mL) with stirring. The mixture washeated to reflux for 2.5 hr, cooled to rt, concentrated to about{fraction (2/3)} volume, diluted with water (300 mL) and acidified topH=3 using 1N HCl. The white solid was collected by filtration and driedto afford 6 g (87%) of 5-formyl-4-methyl- 1 H-pyrrole-3-carboxylic acidas a tan solid.

[0508]¹H NMR (300 MHz, DMSO-d₆) δ 12.28 (br s, 1H, C0₂H), 12.13 (br s,1H, NH), 9.68 (s, 1H, CHO), 7.55 (d, J=3.6 Hz, 1H), 3.32 (s, 3H, CH₃).

[0509] MS m/z 153 [M⁺].

[0510] A. General amidation procedure:

[0511] To the solution of 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acidin DMF (0.3M) was added I -ethyl-3-(3-dimethylamino-propylcarbodiimidehydrochloride (EDC, 1.2 equiv.), 1-hydroxybenzotriazole (HOBt, 1.2 eq)followed by the appropriate amine (1.2 eq). The reaction solution wasstirred for 12h, and then DMF solvent was removed. The residue waspurified on a silica gel column eluting with 1-5% methanol indichloromethane to provide the product.

Example B-93-Methyl4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde

[0512]

5-Formyl-4-methyl- 1H-pyrrole-3-carboxylic acid (500 mg, 3.27 mmol)reacted with 1-methylpiperazine (0.43 mL, 3.92 mmol) to give3-methyl-4-(4-methyl-piperazine- 1-carbonyl)-1H-pyrrole-2-carbaldehyde.

[0513]¹HNMR (300 MHz, DMSO-d₆) δ 12.25 (br s, 1H, NH), 9.66 (s, 1H,CHO), 7.35 (s, 1H), 3.7 (m, 4H, 2×CH₂), 3.16 (m, 4H, 2×CH₂), 2.73 (s,3H, CH₃), 2.32 (s, 3H, CH₃).

[0514] MS 236 [M⁺+1].

Example B-104-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde

[0515]

[0516]5-Formyl-4-methyl-1H-pyrrole-3-carboxylic acid (1.00 g, 6.54 mmol)reacted with cis-2,6-dimethylpiperazine (822 mg, 7.19 mmol) to give4-[(cis)-3,5-dimethyl-piperazine-1 -carbonyl]-3 -methyl-iH-pyrrole-2-carbaldehyde (1.43 g, 88%).

[0517]¹HNMR (300 MHz, DMSO-d6) δ 12.08 (br s, 1H, NH), 9.65 (s, 1H,CHO), 7.23 (s, 1H), 4.09 (br s, 2H, CH₂), 2.62 (m, 2H, CH₂), 2.40 (br s,2H, 2×CH), 2.29 (s, 3H, CH₃), 0.93 (br d, 6H, J=4.6 Hz, 2×CH₃).

[0518] MS m/ 248 [M⁻−1].

Example B-11

[0519] 5-Formyl-4-methyl-1H-pyrrole-2-carboxylic acid

[0520] Step 1: Preparation of 5-Formyl-4-methyl-1H-pyrrole-2-carboxylicacid ethyl ester

[0521] To the ice-cold 3 mL (39.2 mmol) of dimethylformamide (DMF) wasadded phosphorus oxychloride (0.67 mL, 7.18 mmol) drop wise and theresultant mixture was stirred for 30 minutes. A solution of I g (6.53mmol) of 4-methyl-1 H-pyrrole-2-carboxylic acid ethyl ester in 3 mL ofDMF was added to the reaction. After 1 h, the reaction was warmed toroom temperature for another 2.5 h. The reaction mixture was dilutedwith water (100 mL) and basified to pH=11 with IN sodium hydroxidesolution. The precipitate was removed by filtration, rinsing with waterand dried to afford 0.8 g (68%) of5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a whitesolid.

[0522]¹H NMR (360 MHz, DMSO-d₆) δ 12.6 (br s, 1H, NH-1), 9.78 (s, 1H,CHO-5), 6.68 (s, 1H, H-3), 4.26 (q, J=7.0 Hz, 2H, OCH₂CH₃), 2.28 (s, 3H,CH₃-4), 1.28 (t, J=7.0 Hz, 3H, OCH₂CH₃).

[0523] MS m/z 181 (M⁺).

[0524] Step 2: Preparation of 5-Formyl-4-methyl-1H-pyrrole-2-carboxylicacid

[0525] To a solution of 0.8 g (4.4 mmol) of5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester in 35 mL ofwater and 15 mL of ethanol was added 0.5 gram (8.9 mmol) of potassiumhydroxide. The reaction mixture was heated to 100 ° C. for 1 h, cooledto room temperature, and evaporated ethanol. The water layer wasacidified to pH=3 using 2N hydrogen chloride solution. The precipitatewas filtered and washed with water to afford 0.67 g (68%) of5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid as a tan solid.

[0526]¹H NMR (360 MHz, DMSO-d₆) δ 12.92 (br s, 1H, C0₂H-5), 12.48 (br s,1H, NH-l), 9.76 (s, 1H, CHO-5), 6.63 (s, 1H, H-3), 2.28 (s, 3H, CH₃-4).

[0527] MS m/z 152 [M⁻−1].

Example B-12 5-Formyl4-methyl-1H-pyrrole-2-carboxylic acid(2-diethylamino-ethyl)-amide

[0528]

[0529] To a solution of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid(2.50 g, 16.32 mmol) in DMF (54 mL) was added1-ethyl-3-(3-dimethylamino-propylcarbodiimide hydrochloride (EDC, 3.76g, 19.59 mmol), 1-hydroxybenzotriazole (HOBt, 2.65 g, 19.59 mmol)followed by diethylaminoethyl amine (2.75 mL, 19.59 mmol). The reactionsolution was stirred for 12 h, and then DMF solvent was removed. Theresidue was purified on a silica gel column eluting with 1-5% methanolin dichloromethane to provide 3.2 g (78%) of5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid(2-diethylamino-ethyl)-amide.

[0530]¹H NMR (360 MHz, DMSO-d₆) δ 12.22 (br s, 1H, NH), 9.73 (s, 1H,CHO), 8.29 (t, 1H, J=5.5 Hz, CONH), 6.66 (s, 1H, H-3), 3.28 (m, 2H,CH₂), 2.50 (m, 6H, 3×CH₂), 2.30 (s, 3H, CH₃), 0.94 (t, 6H, J=7.2 Hz,2×CH₃).

[0531] MS m/z 252 [M⁺+1].

[0532] B. General amidation procedure:

[0533] To the solution of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acidin DMF (0.3M) was added 1-ethyl-3-(3-dimethylamino-propylcarbodiimidehydrochloride (EDC, 1.2 equiv.), 1-hydroxybenzotriazole (HOBt, 1.2 eq)followed by the appropriate amine (1.2 eq). The reaction solution wasstirred for 12h, and then DMF solvent was removed. The residue waspurified on a silica gel column eluting with 1-5% methanol indichloromethane to provide the product.

Example B-13 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide

[0534]

[0535] 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (3.0 g, 19.6 mmol)reacted with N,N-diethylethylenediamine (3.03 mL, 21.5 mmol) to give2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (4.65 g, 94%).

[0536]¹HNMR (400 MHz, DMSO-d₆) δ 12.16 (br s, 1H, NH), 9.96 (s, 1H,CHO), 8.28 (m, 1H, CONH), 6.40 (s, 1H, H-4), 3.27 (m, 2H, CH₂), 2.49 (m,6H, 3×CH₂), 2.22 (s, 3H, CH₃), 0.95 (t, 6H, J =7.1 Hz, 2×CH₃)

[0537] MS m/z 252 [M⁺+1].

Example B-14 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide

[0538]

2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (3.0 g, 19.6 mmol)reacted with 1-(2-aminoethyl)pyrrolidine (2.73 mL, 21.5 mmol) to give2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (3.71 g, 76%).

[0539]¹HNMR (400 MHz, DMSO-d₆) δ 12.16 (br s, 1H, NH), 9.96 (s, 1H,CHO), 8.32 (m, 1H, CONH), 6.42 (s, 1H, H-4), 3.31 (m, 2H, CH₂), 2.54 (m,6H, 3×CH₂), 2.23 (s, 3H, CH₃), 1.66 (m, 4H, 2×CH₂)

[0540] MS m/z 250 [M⁺+1].

Example B-15 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1 -yl-ethyl)-amide

[0541]

2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2.0 g, 13.06 mmol)reacted with 2-[1,2,3]triazol-1-yl-ethylamine (1.76 g, 15.67 mmol) togive 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (2.55 g, 79%).

[0542]¹HNMR (400 MHz, DMSO-d₆) δ 12.17 (br s, 1H, NH), 9.90 (s, 1H,CHO), 8.32 (t, 1H, J=5.6 Hz, CONH), 8.10 (d, 1H, J=0.85 Hz, triazoleCH), 7.70 (d, 1H, J =0.85 Hz, triazole CH), 6.37 (s, 1H, H-4), 4.56 (m,2H, CH₂), 3.65 (m, 2H, CH₂), 2.22 (s, 3H, CH₃).

[0543] MS m/z248[M⁺+1].

Example B-163-1(3R)-3-Dimethylamino-pyrrolidine-l-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde

[0544]

[0545] 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (536 mg, 3.50mmol) reacted with (3R)-(+)-3-dimethylamino-pyrrolidine (480 mg, 4.20mmol) to give 3-[(3R)-3-dimethylamino-pyrrolidine- 1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (600 mg, 69%).

[0546]¹HNMR (400 MHz, DMSO-d₆) δ 12.23 (br s, 1H, NH), 9.63 (s, 1H,CHO), 6.28 (s, 1H, H-4), 3.89 (m, 2H, CH₂), 3.70 (m, 2H, CH₂), 2.76 (m,7H, 2×CH₃ and CH), 2.229 (m, 9 (m, 1H, CH₂), 2.24 (s, 3H, CH₃), 2.15 (m,1H, CH₂).

[0547] MS m/z 250 [M⁺+1].

Example B-173-[(3S)-3-Dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde

[0548]

[0549] 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (548 mg, 3.58mmol) reacted with (3S)-(−)-3-dimethylamino-pyrrolidine (490 mg, 4.29mmol) to give3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde(460 mg, 52%).

[0550]¹ HNMR (400 MHz, DMSO-d₆) δ 12.22 (br s, 1H, NH), 9.63 (s, 1H,CHO), 6.28 (s, 1H, H-4), 3.90 (m, 2H, CH₂), 3.73 (m, 2H, CH₂), 2.73 (m,7H, 2×CH₃ and CH), 2.28 (m, 1H, CH₂), 2.24 (s, 3H, CH₃), 2.21 (m, 1H,CH₂).

[0551] MS m/z 250 [M⁺+1].

Example B-183-[(cis)-3,5-Dimethyl-piperazine-l-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde

[0552]

[0553] 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (1.00 g, 6.53mmol) reacted with cis-2,6-dimethylpiperazine (900 mg, 7.84 mmol) togive3-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde(1.20 g, 74%).

[0554]¹HNMR (400 MHz, DMSO-d₆) δ 12.12 (br s, 1H, NH), 9.40 (s, 1H,CHO), 6.05 (s, 1H, H-4), 4.15 (m, 1H, CH₂), 3.65 (m, 1H, CH₂), 2.59 (m,2H, CH₂), 2.30 (m, 2H, 2×CH), 2.24 (s, 3H, CH₃), 0.94 (m, 7H, 2×CH₃ andNH).

[0555] MS m/z 250 [M⁺+1].

Example B-193,5-Dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde

[0556]

[0557] 3-(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (1.37 g,6.50 mmol) reacted with 1-methylpiperazine (719.6 mg, 7.15 mmol) to give3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde (1.30 g, 72%).

[0558]¹HNMR (400 MHz, DMSO-d₆) δ 11.40 (br s, H, NH), 9.42 (s, 1H, CHO),3.41 (m, 2H1, CH₂), 3.31 (m, 211, CH₂), 2.54 (m, 2H, CH₂), 2,37 (m, 2H,CH1₂), 2.19 (s, 3H, CH₃), 2.18 (m, 2H, CH₂), 2.15 (s, 3H, CH₃), 2.12 (s,3H, CH₃).

[0559] MS m/z 278 [M⁺+1].

Example B-203,5-Dimethyl-4-[3-[(cis)-3,5-dimethyl-piperazin-1-yl)]-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde

[0560]

[0561] 3-(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (1.37 g,6.50 mmol) reacted with cis-2,6-dimethylpiperazine (822 mg, 7.15 mmol)to give 3,5-dimethyl-4-[3-[(cis)-3,5-dimethyl-piperazin- 1-yl)]-3-oxo-propyl]- 1 H-pyrrole-2-carbaldehyde (1.42 g, 75%).

[0562]¹HNMR (400 MHz, DMSO-d₆) δ 11.39 (br s, 1H, NH), 9.42 (s, 1H,CHO), 1H, CH₂), 3.54 (m, 1H, CH₂), 2.54 (m, 2H, CH₂), 2.45 (m, 2H,2×CH), 2.36 (m, 4H, 2×CH₂), 2.20 (s, 3H, CH₃), m2.14 (s, 3H, CH₃), 1.94(t, 1H, J=11.5 Hz, NH), 0.93 (d, 3H, J=5.9 Hz, CH₃), 0.88 (d, 3H, J=5.6Hz, CH₃).

[0563] MS mi 292 [M⁺+1].

Example B-214-(3-Piperidin-1-yl-propionyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-blazepine-2-carbaldehyde

[0564]

[0565] To a stirred solution of 1,5,6,7-tetrahydro-indol-4-one (5.4 g)in pyridine (40 mL) was added hydroxyammonium chloride (2 eq.) at rt.After 2 hours, the solvent was removed and the residue was diluted withwater and extracted with ethyl acetate. The combined extracts werewashed with brine, dried and concentrated to give 5.5 g of1,5,6,7-tetrahydro-indol-4-one oxime as a pale yellow solid.

[0566]¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (br s, 1H, NH), 9.85 (s, 1H,N—OH), 6.66 (m, 1H), 6.58 (m, 1H), 2.62 (m, 2H), 2.28 (m, 2H), 1.82 (m,2H).

[0567] MS m/z 151.01 [M⁺+1].

[0568] To a stirred solution of 1,5,6,7-tetrahydro-indol-4-one oxime(1.2 g, 7.7 mmol) in DCM (anhydrous, 250 mL) was added DIBAL-H (1 Msolution in DCM, 35 mL) at 0° C. under nitrogen. After 2 hours, NaF (7g)was added followed by water (2.24 g). After 20 mins, the reaction wasfiltered through celite and the solvent was removed to give 350 mg of1,4,5,6,7,8-hexahydro-pyrrolo[3,2-β]azepine as a brown oil.

[0569]¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H, NH), 6.14 (m, 1H), 5.47(m, 1H), 4.2 (br s, 1H, NH), 2.78 (m, 2H), 2.47 (m, 2H), 1.60 (m, 2H),1.46 (m, 2H).

[0570] To a solution of 3-piperidin-1-yl-propionic acid (472 mg, 3 mmol)in DCM (15 mL) at 0° C. was added oxalyl chloride (4.5 mmol) followed byone drop of DMF. After stirring for 2 hours at rt, the solvent wasremoved to give 3-piperidin-1-yl-propionyl chloride as a white solid. Toa solution of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (347 mg, 2.55mmol) in DCM (10 mL) was added TEA (1 eq.) and 1-piperidinepropionicacid chloride. The mixture was stirred at rt for overnight. The reactionwas diluted with DCM, washed with NaHCO₃, brine, dried and concentrated.The residue was purified on a silica gel column to give 230 mg of3-piperidin-1-yl-1-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepin-4-yl)-propan-1-one as a light brown gel.

[0571]¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s, 1H, NH), 6.42 (m, 1H), 5.91(m, 1H), 3.45 (m, 2H), 2.56 (m, 2H), 2.41 (m, 4H), 2.19 (m, 4H), 1.66(m, 2H), 1.51 (m, 2H), 1.40 (m, 4H), 1.29 (m, 2H).

[0572] MS m/z 276.4 [M⁺+1].

[0573] 3-Piperidin-1 -yl- 1-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepin-4-yl)-propan-1 -one (225mg, 0.8 mmol) was formylated with POCl₃ (91 μL, 1.2 eq.) and DMF(1 mL)using standard Vilsmierer condition to give 96 mg of4-(3-piperidin-1-yl-propionyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehydeas a light yellow solid.

[0574]¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (br s, 1H, NH), 9.30 (s, 1H,NH), 6.96 (s, 1H), 3.48 (m, 2H), 2.67 (m, 2H), 2.43 (m, 4H), 2.17 (m,4H), 1.69 (m, 2H), 1.56 (m, 2H), 1.40 (m, 4H), 1.31 (m, 2H).

[0575] MS m/z 304.4 [M⁺+1].

Example B-224-((S)-Pyrrolidine-2-carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-bhazepine-2-carbaldehyde

[0576]

[0577] To a solution of(S)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (664 mg) in DCM (10 mL) at 0 ° C. was added oxalylchloride (4.7 mmol), followed by one drop of DMF. After stirring at rtfor 2 hours, the solvent was concentrated to giveS)-2-chlorocarbonyl-pyrrolidine- 1 -carboxylic acid tert-butyl ester. Toa solution of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (350 mg, 2.6mmol) was added TEA (362 μL) and(S)-2-chlorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester(dissolved in 10 mL of DCM). After stirring at rt for overnight, thereaction was diluted with DCM, washed with NaHCO₃, brine, dried andconcentrated. The residue was purified on a silica gel column to give410 mg of(S)-2-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-pyrrolidine-1 -carboxylic acid tert-butyl ester as a light brown liquid.

[0578] MS m/z 232.5 [M⁺-Boc].

[0579](S)-2-(5,6,7,8-Tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (400 mg, 1.2 mmol) was formylated with POCl₃ (134μL, 1.2 eq.) using standard Vilsmierer condition to give 225 mg of4-((S)-pyrrolidine-2-carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde as a lightyellow solid.

[0580] MS m/z 260.4 [M−1].

Example B-234-(1-Acetyl-piperidine4-carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-blazepine-2-carbaldehyde

[0581]

[0582] To a mixture of l-acetyl-piperidine-4-carboxylic acid (822 mg,4.8 mmol, 1.2 eq.), EDC (920 mg, 1.2 eq.), HOBt (648 mg, 1.2 eq.) in DCM(15 mL) was added TEA (1.3 mL, 2 eq.) and1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (550 mg, 4 mmol). Themixture was stirred at rt for 2 days. The reaction was diluted with DCM,washed with water, sat. NaHCO₃, brine, dried and concentrated. Theresidue was purified on a silica gel column to give 1.1 g of1-[4-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-piperidin-1-yl]-ethanoneas a white solid.

[0583] MS m/z 290.2 [M⁺+1].

[0584]1-[4-(5,6,7,8-Tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-piperidin-1-yl]-ethanone(1.1 g) was formylated with POCl₃ (186,μL, 1.2 eq.) and DMF usingstandard Vilsmierer condition to give 240 mg of4-(1-acetyl-piperidine-4-carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehydeas a gold colored solid.

[0585] MS m/z 318.2 [M⁺+1].

Example B-244-(2-Pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde

[0586]

[0587] To a mixture of 1,5,6,7-tetrahydro-4H-indol-4-one (2.7 g, 20mmol) and tosyl chloride (3.8 g, 20 mmol) in THF (30 mL) was added DIPEA(5.3 mL, 30 mmol). After heating at 70 ° C. for 18 hours, the solventwas removed and the residue dissolved in ethyl acetate, washed (3×) withNaHCO₃ (sat.). The solid was recrystallized to give 4.35 g of1-(p-tosyl)-1,5,6,7-tetrahydro-indol-4-one as a brown solid.

[0588]¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (d, 2H), 7.48 (d, 2H), 7.41 (d,1H), 6.51 (d, 1H), 2.95 (t, 2H), 2.39 (s, 3H, CH₃), 2.33 (t, 2H), 1.99(m, 2H).

[0589] MS m/z 290 [M⁺+1].

[0590] Triethyl phosphonoacetate (9.5 mL, 48 mmol) was added to sodiumhydride (60%) suspended in THF (80 mL) at 0 ° C, followed byl-p-tosyl)-1,5,6,7-tetrahydro-indol-4-one (11.56 g, 40 mmol). Themixture was heated to reflux for 18 hours. The reaction was quenchedwith NH₄Cl (sat.) and extracted with ethyl acetate. After washing withNaHCO₃ (sat.) and brine, the solvent was removed and the residue wasrecrystallized to give 8.2 g of as[1-(p-tosyl)-1,5,6,7-tetrahydro-indol-(4E)-ylidene]-acetic acid ethylester a brown solid.

[0591]¹H NMR (400 MHz, DMSO-d₆) δ 7.81 (d, 2H), 7.45 (d, 2H), 7.33 (d,1H), 6.74 (d, 1H), 5.98 (br s, 1H), 4.04 (q, 2H), 2.88 (m, 2H), 2.78 (t,2H), 2.37 (s, 3H. CH₃), 1.73 (m, 2H), 1.17 (t, 3H).

[0592] MS m/z 360 [M⁺+1].

[0593] [1-(p-Tosyl)-1,5,6,7-tetrahydro-indol-(4E)-ylidene]-acetic acidethyl ester (6.2 g) was hydrogenated using 1% Pd-C (0.6 g) in methanol(280 mL) to give 6.5 g of[1-(p-tosyl)-4,5,6,7-tetrahydro-1H-indol-4-yl]-acetic acid ethyl ester.

[0594]¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (d, 2H), 7.42 (d, 2H), 7.21 (brd, 1H), 6.18 (br d, 1H), 4.04 (m, 2H), 2.86 (m, 1H), 2.58 (m, 3H), 2.36(s, 3H, CH₃), 2.23 (dd, 1H), 1.74 (m, 2H), 1.54 (m, 1H), 1.24 (m, 1H),1.14 (t, 3H).

[0595] MS m/z 362 [M⁺+1].

[0596] [1-(p-Tosyl)-4,5,6,7-tetrahydro-1H-indol-4-yl]-acetic acid ethylester (3 g) was hydrolyzed using NaOH (4N, 10 mL) in MeOH (10 mL) andTHF (10 mL) at rt for 1 hour. The reaction was adjusted to pH 3 andextracted with ethyl acetate, dried and concentrated to give 2 g of[1-(p-tosyl)-4,5,6,7-tetrahydro-1H-indol-4-yl]-acetic acid as a whitesolid.

[0597]¹H NMR (400 MHz, DMSO-d₆) δ 7.71 (d, 2H), 7.42 (d, 2H), 7.18 (d,1H), 6.21 (d, 1H), 2.83 (m, 1H), 2.56 (m, 2H), 2.45 (m, 1H), 2.36 (s,3H, CH₃), 2.07 (dd, 1H) 1.73 (m, 2H), 1.52(m, 1H), 1.2 (m, 1H).

[0598] MS m/z 334 [M⁺+1].

[0599] To a mixture of[l-(p-Tosyl)-4,5,6,7-tetrahydro-1H-indol-4-yl]-acetic acid (1 g, 3mmol),HOBt (486 mg, 1.2 eq.), EDC (690 mg, 1.2 eq.) in DMF (5 mL) was addedTEA (1 mL, 2.5 eq.) and pyrrolidine (0.3 mL, 1.2 eq.). The mixture wasstirred at rt for overnight. The reaction was diluted with DCM, washedwith NaHCO₃, citric acid (3% aq.), water, brine, dried and concentrated.The residue was purified on a silica gel column to give 913 mg of1-pyrrolidin-1-yl-2-[l-(toluene-4-sulfonyl)-4,2,6,7-tetrahydro-1H-indol-4-yl]-ethanoneas a white semi-solid.

[0600]¹H NMR (400 MHz, DMSO-d₆) δ 7.73 (d, 2H), 7.43 (d, 2H), 7.19 (d,1H), 6.17 (d, 1H), 3.3 (m, 4H), 2.92 (m, 1H), 2.58 (m, 2H), 2.44 (d,1H), 3.77 (s, 3H, CH₃), 2.18 (dd, 1H), 1.74 (m, 6H), 1.55 (m, 1H), 1.24(m, 1H).

[0601] Pyrrolidin- 1 -yl-2-[1 -(toluene-4-sulfonyl)-4,5,6,7-tetrahydro-1 H-indol-4-yl]-ethonone (840 mg) was reduced using lithium aluminumhydride (4 eq.) in THF (80 mL) at reflux for 5 hours to give 480 mg ofmainly 4-(2-pyrrolidin-1 -yl-ethyl)-4,5,6,7-tetrahydro-1H-indole as anoil.

[0602] MS m/z 373 [M⁺+1].

[0603] 4-(2-Pyrrolidin-l-yl-ethyl)-4,5,6,7-tetrahydro-1H-indole (475 mg,2.2 mmol) was formylated with POCl₃ (0.25 mL, 1.2 eq.) and DMF (2 ml)using standard Vilsmierer condition to give 250 mg of4-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehydeas alight yellow solid.

[0604]¹H NMR (400 MHz, DMSO-d₆) δ 13.63 (br s, 1H, NH), 9.26 (s, 1H,CHO), 6.77 (s, 1H), 4.2 (br s, 1H), 3.15 (s, 2H), 2.5 (m, 6H), 1.83 (m,3H), 1.68 (m, 4H), 1.57 (m, 1H), 1.50 (m, 1H), 1.27 (m, 1H).

[0605] MS m/z [M⁺+1].

General procedure for 3,5-dimethyl-4-methylaminopyrrole aldehydes

[0606]

[0607] A mixture of 3,5-dimethyl-1 H-pyrrole-2-carbaldehyde (20 mmol) inTHF (40 mL), water (20 mL), acetic acid (3 mL), formaldehyde (37% wt. %solution in water, 5 mL) and the appropriate amine (30 mL) was heated toreflux (oil bath 90-100° C.) for 6 hours. The reaction was concentratedto a volume of 30 mL, basified with 2N NaOH and extracted with ethylacetate (2×150 mL) and DCM (4×100 mL). The combined organic layers wereconcentrated and the residue was purified on a silica gel column to givethe desired product.

Example B-25 4-(4-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde

[0608]

[0609] A mixture of 3,5-dimethyl-1 H-pyrrole-2-carbaldehyde (2.5 g, 20mmol) in THF (40 mL), water (20 mL), acetic acid (3 mL), formaldehyde(37% wt. % solution in water, 5 mL) and the appropriate amine (30 mL)was heated to reflux (oil bath 90-100° C.) for 6 hours and then stirredat rt for overnight. The reaction was concentrated to a volume of 30 mL,basified with 2 N NaOH and extracted with ethyl acetate (2×150 mL) andDCM (4×100 mL). The combined organic layers were concentrated and theresidue was purified on a silica gel column to give 2.3 g (49%) of4-(4-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde as a solid.

[0610]¹ H NMR (400 MHz, DMSO-d₆) δ 11.50 (br s5, H, NH), 9.43 (s,1 H,CHO), 4.5 0 (br s, 1 H), 3.41 (v br s, 1 H, OH), 3.15 (s, 2 H), 2.60 (m,2 H), 2.22 (s, 3 H, CH₃), 2.16 (s, 3 H, CH₃),1.94 (0, 2 H), 1.66 (m, 2H), 1.27 (m, 2 H).

Example B-26 3,5-Dimethyl-4-morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde

[0611]

[0612] A mixture of 3,5-dimethyl-1 H-pyrrole-2-carbaldehyde (1.85 g, 15mmol), di-morpholine-methane (5 mL, 27 mL) in THF (40 mL), water (15 mL)and acetic acid (4 mL) was heated to reflux (oil bath 90-95° C.) for 6hours. The reaction was concentrated to a volume of 20 mL, basified withNa₂CO₃ and extracted with ethyl acetate (3×75 mL). The combined extractswere dried, concentrated and the residue was purified on a silica gelcolumn to give 2 g (36%) of 3,5-dimethyl-4-morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde as a solid.

[0613]¹ H NMR (400 MHz, DMSO-d₆) δ 11.51 (br s, 1 H, NH), 9.44 (s, 1 H,CHO), 3.51 (m, 4 H), 3.19 (s, 2 H), 2.28 (m, 4 H), 2.23 (s, 3 H, CH₃),2.17 (s, 3 H, CH₃).

Example B-27 3,5-Dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin4-yl)-1H-pyrrole-2-carbaldehyde

[0614]

[0615] To a solution of 3,5-dimethyl-1 H-pyrrole-2-carboxylic acid ethylester (836 mg, 5 mmol) in acetic acid (10 mL) and TFA (5 mL) undernitrogen was added 1-methyl-piperidin-4-one (0.8 mL, 6.67 mmol). Themixture was then heated in a 95° C. oil bath for overnight. The reactionwas concentrated, dissolved in ethyl acetate, washed with NaHCO₃, brine,dried and concentrated. The residue was purified on a silica gel columnto give 1.12 g (85%) of3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid ethyl ester.

[0616]¹ H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1 H, NH), 5.49 (m, 1 H), 4.29(q, 2 H), 3.09 (m, 2 H), 2.63 (t, 2 H), 2.41 (s, 3 H, CH₃), 2.34 (m, 2H), 2.26 (s, 3 H, CH₃), 2.21 (s, 3 H, CH₃), 1.34 (t, 3 H).

[0617] MS m/z 263 [M⁺+1].

[0618] A mixture of3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (1.02 g, 3.9 mmol), KOH (0.287g, 5.1 mmol) in water (5 mL) and methanol (10 mL) was heated to refluxunder nitrogen for 3 days. The cooled reaction was extracted with ethylacetate (3×), dried and concentrated to give 380 mg of 4-(2,4-dimethyl-1H-pyrrol-3-yl)-1-methyl-1,2,3,6-tetrahydro-pyridine. The aqueous layerwas adjusted to pH 7, the resulted precipitate was collected byfiltration, washed with water to give 380mg of 4-(2,4-dimethyl-1H-pyrrol-3-yl)-1-methyl-1,2,3,6-tetrahydro-pyridine and 480 mg of3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid.

[0619]¹ H NMR (400 MHz, DMSO-d₆) δ 10.05 (br s, 1 H, NH), 6.25 (s, 1 H),5.30 (m,1 H), 2.92 (m, 2 H), 2.48 (m, 2 H), 2.24 (m, 2 H), 2.23 (s, 3 H,CH₃), 2.06 (s, 3 H, CH₃), 1.88 (d, 3 H, CH₃).

[0620] Triethyl orthoformate (6 mL) was added to a solution of4-(2,4-dimethyl-1 H-pyrrol-3-yl)-1-methyl-1,2,3,6-tetrahydro-pyridine(360 mg) in TFA (6 mL) at 0° C. The mixture was stirred at 0° C. for 10mins and then at rt for 40 mins. The solvent was removed and to theresidue was added NaHCO₃, extracted with ethyl acetate, dried andconcentrated to give 356 mg of3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carbaldehyde.

[0621]¹ H NMR (400 MHz, CDCl₃) δ 9.49 (s, 1 H, CHO), 9.10 (br s, 1 H,NH), 5.52 (m, 1 H), 3.12 (m, 2 H), 2.66 (t, 2 H), 2.43 (s, 3 H), 2.35(m, 2 H), 2.26 (s, 3 H), 2.24 (s, 3 H).

Example B-28 3,5-Dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrole-2-carbaldehyde

[0622]

[0623] 3,5-Dimethyl-1 H-pyrrole-2-carboxylic acid ethyl ester (7.97 g)in methanol (200 mL) and acetic acid (5 mL) was hydrogenated using 10%Pd-C at rt overnight to give 10.25 g of3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1 H-pyrrole-2-carboxylic acidethyl ester as acetic acid salt.

[0624]¹ H NMR (400 MHz, DMSO-d₆) δ 10.97 (br s, 1 H, NH), 4.15 (q, 2 H),2.84 (m, 2 H), 2.35 (m, 1 H), 2.20 (s, 3 H, CH₃), 2.18 (s, 3 H, CH₃),2.15 (s, 3 H, CH₃), 1.95 (m, 2 H), 1.82 (m, 2 H), 1.47 (m, 2 H), 1.23(t, 3 H).

[0625] MS m/z 265 [M⁺+1].

[0626] A solution of 3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrole-2-carboxylic acid ethyl ester, di-acetic acid salt (4.87 g,12.67 mmol), LiOH (1.8 g, 75 mmol) in methanol (20 mL) and water (10 mL)was heated in a 90° C. oil bath for 6 hours. The cooled reaction wasadjusted to pH 7 with 6 N HCl and concentrated to give3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1 H-pyrrole-2-carboxylic acid,LiCl salt. This was used in the next step without further purification.

[0627] A solution of 3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrole-2-carboxylic acid (12.67 mmol) in TFA (75 mL) was stirred at0° C. for 30 mins. To the mixture was added triethyl orthoformate (20mL), it was then allowed to warm up slowly to rt for 2 hours. Thesolvent was removed and to the residue was added NaHCO₃, extracted withethyl acetate, dried and concentrated to give 2.56 g of3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1 H-pyrrole-2-carbaldehyde as alight yellow solid.

[0628]¹ H NMR (400 MHz, DMSO-d₆) δ 11.43 (br s, 1 H, NH), 9.41 (s, 1 H,CHO), 2.82 (m, 2 H), 2.65 (m, 5 H), 2.24 (s, 3 H, CH₃), 2.19 (s, 3 H,CH₃), 1.95 (m, 3 H), 1.64 (m, 2 H).

Example B-29 (2-Formyl-5-methyl-1 H-pyrrol-3-yl)-acetic acid

[0629]

[0630] A solution of 3-ethoxycarbonylmethyl-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (7 g, 29.26 mmol), LiOH (7 g, 10eq.) in methanol (90 mL) and water (30 mL) was heated in a 70° C. oilbath for 3 hours. The cooled reaction was adjusted to pH 3 with 3 N HCl,the resulted precipitate was collected by filtration, washed with waterand dried to give 4.67 g (87%) of 3-carboxymethyl-5-methyl-1H-pyrrole-2-carboxylic acid.

[0631]¹ H NMR (400 MHz, DMSO-d₆) δ 11.88 (s, 2 H, 2×COOH), 11.2 (s, 1 H,NH), 5.68 (s, 1 H), 3.6 (s, 2 H), 2.14 (s, 3 H, CH₃).

[0632] MS m/z 182 [M−1].

[0633] A suspension of 3-carboxymethyl-5-methyl-1 H-pyrrole-2-carboxylicacid (1.5, 8.2 mmol) in TFA (6 mL) was heated under nitrogen in a 55° C.oil bath until all of the solid had dissolved and no more CO₂ gas givenoff. The reaction was cooled to 0° C. and used in the next step.

[0634] To a solution of (5-methyl-1 H-pyrrol-3-yl)-acetic acid (8.2mmol) in TFA (6 mL) at 0° C. was added triethyl orthoformate (6 mL), itwas then at 0° C. for 10 mins and at rt for 0.5 hours. The reaction waspoured into water, extracted with ethyl acetate, dried and concentrated.The residue was purified on a silica gel column to give 1.15 g (84%) of(2-formyl-5-methyl-1 H-pyrrol-3-yl)-acetic acid.

[0635]¹ H NMR (400 MHz, DMSO-d₆) δ 12.26 (br s, 1 H, COOH), 11.67 (s, 1H, NH), 9.41 (s, 1 H, CHO), 5.90 (d, 1 H), 3.64 (s, 2 H), 2.18 (s, 3 H,CH₃).

Example B-30 5-Formyl-4-(3-methanesulfonyl-propyl)-2-methyl-1H-pyrrole-3-carboxylic acid

[0636]

[0637] Oxone (614 mg, 1 mmol) dissolved in water (2 mL) was addedportionwise to a solution of5-formyl-2-methyl-4-(3-methylsulfanyl-propyl)-1 H-pyrrole-3-carboxylicacid ethyl ester (269 mg, 1 mmol) in methanol (4 mL) cooled in an icebath. The mixture was stirred for 3 hours, keeping the temp between 0°C. and rt. The reaction was diluted with 10 mL of water, the resultedprecipitate was collected by vacuum filtration, washed with water anddried to give 95 mg of the desired product. The water filtrate wasextracted with ethyl acetate, dried and concentrated to give another 74mg of the product. Total of 169 mg (56%) of5-formyl-4-(3-methanesulfonyl-propyl)-2-methyl-1 H-pyrrole-3-carboxylicacid ethyl ester was obtained.

[0638]¹ H NMR (400 MHz, DMSO-d₆) δ 12.26 (br s, 1 H, NH), 9.61 (s, 1 H,CHO), 4.19 (q, 2 H), 3.06 (m, 4 H), 2.93 (s, 3 H, CH₃), 2.42 (s, 3 H,CH₃), 1.93 (m, 2 H), 1.27 (t, 3 H).

[0639] Lithium hydroxide (179.6 mg, 7.5 mmol) was added to a suspensionof5-formyl-4-(3-methanesulfonyl-propyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (450 mg, 1.5 mmol) in methanol(6 mL) and water (6 mL). The mixture was heated under nitrogen in a 65°C. oil bath for 20 hours. The cooled reaction was adjusted to pH 2 using1 N HCl, the resulted precipitate was collected by vacuum filtration,washed with water and dried to give 356 mg (87%) of5-formyl-4-(3-methanesulfonyl-propyl)-2-methyl-1 H-pyrrole-3-carboxylicacid.

[0640]¹ H NMR (400 MHz, DMSO-d₆) δ 12.20 (br s, 2 H, OH, NH), 9.59 (s, 1H, CHO), 3.07 (m, 4 H), 2.92 (s, 3 H, CH₃), 2.41 (s, 3 H, CH₃), 1.96 (m,2 H).

General Procedure for the Synthesis of 3-Substituted4-Aryl-1,3-dihydro-indol-2-one

[0641]

[0642] To a solution of 4-aryl-l1,3-dihydro-indol-2-one (1 molarequivalent) and pyrrole aldehyde (1 molar equivalent in ethanol (0.125M) was added catalytic amount of piperidine. The reaction mixture wasstirred at room temperature for three days, and a yellow solid productwas precipitated out, or a yellow solution was observed. If it wasprecipitated out, the yellow solid product was filtered, washed byethanol, and dried under high vacuum. If it was not precipitated, theproduct was purified on a silica gel column eluting with MeOH—CH₂Cl₂.

Example 12-Methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-5-(2-oxo-4-phenyl-1,2-diiydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid ethyl ester

[0643]

[0644] To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20mmol) and 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (64.2 mg, 0.20 mmol) in ethanol(1 mL) was added piperidine (0.1 mL). The reaction mixture was stirredat 70° C. for over-night. The solvent was evaporated and the residue waspurified on a silica gel column eluting with MeOH—CH₂CL₂ 1:9 to provide2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid ethyl ester as a yellow solid (30 mg, 29%).

[0645]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.85 (br s, 1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 7.53 (m, 3 H, aromatic), 7.44 (m, 2 H, aromatic),7.21 (t, 1 H, aromatic), 6.94 (d, 1 H, aromatic), 6.89 (s, 1 H,aromatic), 6.78 (d, 1 H, aromatic), 4.24 (q, 2 H, OCH₂), 2.50 (m, l1 H,3×CH₂+CH₃), 2.33 (s, 3 H, CH₃), 2.10 (m, 4 H, 2×CH₂), 1.26 (m, 5 H,CH₂+CH₃).

[0646] MS m/z 511 [M⁻−1].

Example 2 3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one

[0647]

[0648] To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (49.9 mg, 0.20 mmol) in ethanol (1 mL) wasadded piperidine (0.1 mL). The reaction mixture was stirred at 70° C.for over-night. The solvent was evaporated and the residue wascrystallized from EtOAc—hexanes to provide3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one as a yellowsolid (50 mg, 57%).

[0649]¹ H-NMR (400 MHz, CD₃OD) δ 7.53 (m, 2 H, aromatic), 7.47 (m, 1 H,aromatic), 7.40 (m, 2 H, aromatic), 7.18 (t, 1 H, aromatic), 6.93 (d, 1H, aromatic), 6.87 (s, 1 H, aromatic), 6.81 (d, 1 H, aromatic), 3.71 (brs, 2 H, CH₂), 3.45 (br s, 2 H, CH₂), 2.42 (br s, 4 H, 2×CH₂), 2.30 (s, 3H, CH₃), 2.28 (s, 3 H, CH₃), 1.60 (s, 3 H, CH₃).

[0650] MS m/z 441 [M⁺+1].

Example 32,4-Dimethyl-5-(2-oxo4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0651]

[0652] To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (53.1 mg, 0.20 mmol) in ethanol (1 mL) wasadded piperidine (0.1 mL). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide2,4-dimethyl-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid (2-diethylarnino-ethyl)-amide (51 mg, 56%)

[0653]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.03(br s, 1 H, CONH), 7.43 (m, 6 H, aromatic), 7.18 (t, 1 H, CONH), 7.18(t, 1 H, aromatic), 6.93 (m, 1 H, aromatic), 6.77 (m, 2 H, aromatic),3.21 (m, 2 H, CH₂), 2.48 (m, 6 H, 3×CH₂), 2.38 (s, 3 H, CH₃), 1.66 (s, 3H, CH₃), 0.87 (t, 6 H, 2×CH₃).

[0654] MS m/z 455 [M⁻−1].

Example 4 3-[3,5-Dimethyl4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one

[0655]

[0656] To a solution of 4-(4-fluoro-phenyl)-I,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and3,5-dimethyl-4-(4-methyl-piperazine-l1-carbonyl)-1H-pyrrole-2-carbbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide 3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl) 1,3-dihydro-indol-2-one as ayellow solid (63.9 mg, 56%)

[0657]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.45 (br s,1 H, pyrrole NH), 11.04(br s,1 H), 7.47 (m, 2 H, aromatic), 7.39 (m, 2 H, aromatic), 7.19 (t, 1H, aromatic), 6.92 (m, 1 H, aromatic), 6.79 (m, I1 H, aromatic), 6.71(s, I1 H, aromatic), 3.31 (s, 4 H, 2×CH₂), 2.3 (m, 7 H, 2×CH₂+CH₃), 2.17(s, 3 H, CH₃), 1.60 (s, 3 H, CH₃).

[0658] MS m/z 457 [M⁻−1].

Example 5 5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0659]

[0660] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (82.9 mg, 70%)

[0661]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1 H, pyrrole NH), 11.04(br s, 1 H, CONH), 7.46 (m, 2 H, aromatic), 7.38 (m, 2 H, aromatic),7.32 (t, 1 H, CONH), 7.18 (t, 1 H, aromatic), 6.93 (m, 1 H, aromatic),6.79 (m, 1 H, aromatic), 6.71 (s, 1 H, aromatic), 3.20 (m, 2 H, CH₂),2.49 (m, 6 H, 3×CH₂), 2.39 (s, 3 H, CH₃), 1.74 (s, 3 H, CH₃), 0.95 (t, 6H, 2×CH₃).

[0662] MS m/z 473 [M⁻−1].

Example 65-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[0663]

[0664] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mm(l) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (90.0 mg, 76%).

[0665]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.46 (br s, 1 H, pyrrole NH), 11.04(br s, 1 H, CONH), 7.42 (m, 5 H, aromatic+CONH), 7.18 (t, 1 H,aromatic), 6.92 (m, 1 H, aromatic), 6.79 (m, 1 H, aromatic), 6.71 (s, 1H, aromatic), 3.32 (m, 2 H, CH₂), 2.49 (m, 2 H, CH₂), 2.45 (m, 4 H,2×CH₂), 2.38 (s, 3 H, CH₃), 1.73 (s, 3 H, CH₃), 1.67 (m, 4 H 2×CH₂)

[0666] MS m/z 471 [M⁻−1].

Example 75-[4-(4-Fluorophenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,31triazol-1-yl-ethyl)-amide

[0667]

[0668] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1 -yl-ethyl)-amide (67.9 mg, 0.26 mmol) inethanol (2 mL) was added piperidine (3 drops). The reaction mixture w asstirred at room temperature for three days. A yellow solid product wasprecipitated out, filtered, washed by ethanol for three times, and driedunder high vacuum to provide pure product5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (42.8 mg, 36%).

[0669]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1 H, pyrrole NH), 11.04(br s, 1 H, CONH), 8.10 (m, 1 H, aromatic), 7.71 (m, 1 H, aromatic),7.61 (m, 1 H, CONH), 7.60 (m, 2 H, aromatic), 7.38 (m, 2 H, aromatic),7.20 (m, 1 H, aromatic), 6.93 (m, 1 H, aromatic), 6.78 (m, 1 H,aromatic), 6.70 (s, 1 H, aromatic), 4.53 (m, 2 H, CH₂), 3.63 (m, 2 H,CH₂), 2.30 (s, 3 H, CH₃), 1.65 (s, 3 H, CH₃). MS m/z 469 [M⁻−1].

Example 84-(4-Fluoro-phenyl)-3-[5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0670]

[0671] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product4-(4-fluoro-phenyl)-3-[5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (44.1mg, 40%).

[0672]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.63 (br s, 1 H, pyrrole NH), 11.10(br s, 1 H, CONH), 7.40 (m, 2 H, aromatic), 7.24 (m, 3 H, aromatic),6.97 (s, 1 H, vinyl), 6.91 (m, 1 H, aromatic), 6.75 (m, 1 H, aromatic),6.07 (s, 1 H, aromatic), 3.44, 3.30 (2×m, 4 H, 2×CH₂), 2.32 (s, 3 H,CH₃), 2.18 (m, 7 H, 2×CH₂+CH₃).

[0673] MS m/z 443 [M⁻−1].

Example 92-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[0674]

[0675] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product as a yellow solid2-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (74.3mg, 65%).

[0676]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.84 (br s, 1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 7.98 (m, 2 H, aromatic), 7.93 (s, 1 H, aromatic),7.73 (m, 1 H, aromatic), 7.38 (m, 2 H, aromatic), 7.23 (m, 3 H,aromatic+CONH), 6.92 (m, 1 H, aromatic), 6.77 (m, 1 H, aromatic), 6.32(m, 1 H, aromatic), 4.53 (m, 2 H, CH₂), 3.63 (m, 2 H, CH₂), 2.30 (s, 3H, CH₃), 1.65 (s, 3 H, CH₃).

[0677] MS m/z 455 [M⁻−1].

Example 10 3-[3-((S)-3-Dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one

[0678]

[0679] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and3-[3-(3S)-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product3-[3-[3-(3S)-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (64.4 mg, 56%).

[0680]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.69 (br d, 1 H, pyrrole NH), 11.10(br s, 1 H, CONH), 7.40 (m, 2 H, aromatic), 7.20 (m, 4 H, aromatic),6.92 (m, 1 H, aromatic), 6.75 (m, 1 H, aromatic), 6.20 (m, 1 H,aromatic), 3.30 (m, 4 H, 4×CH), 3.00 (m, 1 H, CH), 2.60 (m, 1 H, CH),2.33 (s, 3 H, CH₃), 2.21 (s, 3 H, CH₃), 2.08 (s, 3 H, CH₃), 1.64 (m, 1H, CH).

[0681] MS m/z 457 [M⁻−1].

Example 11 3-[3-((R)-3-Dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one

[0682]

[0683] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and3-[3-(3R)-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product3-[3-[3-(3R)-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (63.9, 56%).

[0684]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.69 (br d, 1 H, pyrrole NH), 11.10(br s, 1 H, CONH), 7.40 (m, 2 H, aromatic), 7.20 (m, 4 H, aromatic),6.92 (m, 1 H, aromatic), 6.75 (m, 1 H, aromatic), 6.20 (m, 1 H,aromatic), 3.33 (m, 4 H, 4×CH), 3.00 (m, 1 H, CH), 2.60 (m, 1 H, CH),2.33 (s, 3 H, CH₃), 2.21 (s, 3 H, CH₃), 2.08 (s, 3 H, CH₃), 1.64 (m, 1H, CH).

[0685] MS m/z 457 [M−1].

Example 12 3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]4-(3-fiuoro-phenyl)-1,3-dihydro-indol-2-one

[0686]

[0687] To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (65 mg, 57%)

[0688]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.45 (br s, 1 H, pyrrole NH), 11.06(br s, 1 H, CONH), 7.59 (m, 1 H, aromatic), 7.33 (m, 3 H, aromatic),7.20 (t, 1 H, aromatic), 6.94 (d, 1 H, aromatic), 6.80 (d, 1 H,aromatic), 6.77 (s, 1 H, aromatic), 3.38 (m, 4 H, 2×CH₂), 2.24 (m, 7 H,2×CH₂+CH₃), 2.16 (s, 3 H, CH₃), 1.59 (s, 3 H, CH₃).

[0689] MS m/z 459 [M⁺+1].

Example 135-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole3-carboxylic acid (2-diethylamino-ethyl)-amide

[0690]

[0691] To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (70 mg, 59%)

[0692]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.07(br s, 1 H, CONH), 7.59 (m, 1 H, aromatic), 7.32 (m, 4 H, aromatic),7.20 (t, 1 H, CONH), 6.95 (d, 1 H, aromatic), 6.80 (m, 2 H, aromatic),3.22 (m, 2 H, CH₂), 2.49 (m, 6 H, 3×CH₂), 2.39 (s, 3 H, CH₃), 1.73 (s, 3H, CH₃), 0.95 (t, 6 H, 2×CH₃).

[0693] MS m/z 475 [M⁺+1].

Example 145-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[0694]

[0695] To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (56.4 mg, 48%).

[0696]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1 H, pyrrole NH), 11.06(br s, 1 H, CONH), 7.59 (m, 1 H, aromatic), 7.46 (t, 1 H, CONH), 7.34(m, 3 H, aromatic), 7.20 (t, 1 H, aromatic), 6.95 (d, 1 H, aromatic),6.80 (m, 2 H, aromatic), 3.27 (m, 2 H, CH₂), 2.50 (m, 2 H, CH₂), 2.45(m, 4 H, 2×CH₂), 2.38 (s, 3 H, CH₃), 1.72 (s, 3 H, CH₃), 1.67 (m, 4 H2×CH₂).

[0697] MS m/z 473 [M⁺+1].

Example 155-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[0698]

[0699] To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol(2 mL) was added piperidine (3 drops). The reaction mixture was stirredat room temperature for three days. A yellow solid product wasprecipitated out, filtered, washed by ethanol for three times, and driedunder high vacuum to provide pure product5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (49.9 mg, 42%).

[0700]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1 H, pyrrole NH), 11.06(br s, 1 H, CONH), 8.10 (s, 1 H, aromatic), 7.72 (m, 1 H, aromatic),7.63 (m, 2 H, CONH+aromatic), 7.33 (m, 3 H, aromatic), 7.20 (t, 1 H,aromatic), 6.95 (d, 1 H, aromatic), 6.80 (m, 2 H, aromatic), 4.53 (m, 2H, CH₂), 3.63 (m, 2 H, CH₂), 2.29 (s, 3 H, CH₃), 1.64 (s, 3 H, CH₃).

[0701] MS m/z 471 [M⁺+1].

Example 16 3-[3-((S)-3-Dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[0702]

[0703] To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (60.9 mg, 53%).

[0704]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.63 (br d, 1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 7.47 (m, 1 H, aromatic), 7.21 (m, 5 H, aromatic),6.94 (d, 1 H, aromatic), 6.77 (d, 1 H, aromatic), 6.19 (m, 1 H,aromatic), 3.30 (m, 4 H, 4×CH), 3.00 (m, 1 H, CH), 2.60 (m, 1 H, CH),2.33 (s, 3 H, CH₃), 2.21 (s, 3 H, CH₃), 2.07 (s, 3 H, CH₃), 1.61 (m, 1H, CH).

[0705] MS m/z 459 [M⁺+1].

Example 17 3-[3-((R)-3-Dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[0706]

[0707] To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and3-[(3R)-3-dimethylamino-pyrrolidine-l1-carbonyl]-5-methyl-I1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product3-[3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (63.5, 55%).

[0708]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.64 (br d,1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 7.47 (m, 1 H, aromatic), 7.22 (m, 5 H, aromatic),6.94 (d, 1 H, aromatic), 6.78 (d, 1 H, aromatic), 6.19 (m, 1 H,aromatic), 3.31 (i, 4 H, 4×CH), 3.00 (m, 1 H, CH), 2.60 (m, 1 H, CH),2.33 (s, 3 H, Ch₃),2.21 (s, 3 H, CH₃), 2.07 (s, 3 H, CH₃), 1.61 (m, 1 H,CH).

[0709] MS m/z 459 [M⁺+1].

Example 185-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester

[0710]

[0711] To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (80.3 mg, 0.26 mmol) in ethanol(2 mL) was added piperidine (3 drops). The reaction mixture was stirredat room temperature for three days. A yellow solid product wasprecipitated out, filtered, washed by ethanol for three times, and driedunder high vacuum to provide pure product5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester as a yellow solid (60.9 mg,53%).

[0712]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.85 (br s, 1 H, pyrrole NH), 11.33(br s, 1 H, CONH), 7.58 (m, 1 H, aromatic), 7.32 (m, 3 H, aromatic),7.22 (t, 1 H, aromatic), 6.95 (d, 1 H, aromatic), 6.90 (m, 1 H,aromatic), 6.80 (d, 1 H, aromatic), 4.17 (q, 2 H, OCH₂), 3.30 (s, 1 H,CH₃), 2.26 (m, 1OH, 5×CH₂), 2.11 (s, 3 H, CH₃), 2.00 (m, 2 H, CH₂), 1.26(m, 5 H, CH₂+CH₃).

[0713] MS m/z 531 [M⁺+1].

Example 19 3-[3-(cis)-3,5-Dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[0714]

[0715] To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and3-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 95:5 to providepure product 3-[3-[(cis)-3,5-Dimethyl-piperazine-1-carbonyl)]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (74.5 mg, 65%).

[0716]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.60 (br s, 1 H, pyrrole NH), 11.11(br s, 1 H, CONH), 7.48 (m, 1 H, aromatic), 7.20 (m, 4 H, aromatic),6.94 (m, 2 H, aromatic), 6.77 (d, 1 H, aromatic), 6.06 (d, 1 H,aromatic), 4.13 (m, 1 H, CH), 3.41 (m, 1 H, CH), 2.37 (m, 6 H,CH+CH₂+CH₃), 2.05 (m, 1 H, CH), 1.04 (m, 3 H, CH₃), 0.80 (m, 3 H, CH₃).

[0717] MS m/z 459 [M⁺+1].

Example 204-(4-Chloro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0718]

[0719] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide4-(4-Chloro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (54mg, 45%)

[0720]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.42 (br s, 1 H, pyrrole NH), 11.05(br s, 1 H, CONH), 7.62 (d, 2 H, aromatic), 7.45 (d, 2 H, aromatic),7.19 (t, 1 H, aromatic), 6.95 (d, 1 H, aromatic), 6.79 (d, 1 H,aromatic), 6.66 (s, 1 H, aromatic), 3.31 (m, 4 H, 2×CH₂), 2.38 (m, 7 H,2×CH₂+CH₃), 2.17 (s, 3 H, CH₃), 1.60 (s, 3 H, CH₃).

[0721] MS m/z 475 [M⁺+1].

Example 215-[4-(4-Chloro-phenyl)-2-oxo1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0722]

[0723] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (59.4 mg, 48%).

[0724]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.44 (br s, 1 H, pyrrole NH), 11.05(br s, 1 H, CONH), 7.61 (m, 2 H, aromatic), 7.44 (m, 2 H, aromatic),7.33 (t, 1 H, CONH), 7.19 (t, 1 H, aromatic), 6.95 (m, 1 H, aromatic),6.80 (m, 1 H, aromatic), 6.71 (s, 1 H, aromatic), 3.20 (m, 2 H, CH₂),2.49 (m, 6 H, 3×CH₂), 2.39 (s, 3 H, CH₃), 1.74 (s, 3 H, CH₃), 0.95 (t, 6H, 2×CH₃).

[0725] MS m/z 491 [M⁺+1].

Example 22 5-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[0726]

[0727] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (54.9 mg, 45%).

[0728]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.43 (br s, 1 H, pyrrole NH), 11.05(br s, 1 H, CONH), 7.61 (m, 2 H, aromatic), 7.44 (m, 3 H, aromatic),7.19 (t, 1 H, aromatic), 6.93 (m, 1 H, aromatic), 6.79 (m, 1 H,aromatic), 6.66 (s, 1 H, aromatic), 3.30 (m, 2 H, CH₂), 2.50 (m, 2 H,CH₂), 2.47 (m, 4 H, 2×CH₂), 2.38 (s, 3 H, CH₃), 1.73 (s, 3 H, CH₃), 1.67(m, 4 H 2×CH₂).

[0729] MS m/z 489 [M⁺+1].

Example 235-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[0730]

[0731] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol(2 mL) was added piperidine (3 drops). The reaction mixture was stirredat room temperature for three days. A yellow solid product wasprecipitated out, filtered, washed by ethanol for three times, and driedunder high vacuum to provide pure product5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (43.4 mg, 36%).

[0732]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.44 (br s, 1 H, pyrrole NH), 11.05(br s, 1 H, CONH), 8.10 (m, 1 H, aromatic), 7.71 (m, 1 H, aromatic),7.62 (m, 3 H, aromatic), 7.46 (m, 2 H, aromatic), 7.20 (m, 1 H,aromatic), 6.93 (m, 1 H, aromatic), 6.78 (m, 1 H, aromatic), 6.65 (s, 1H, aromatic), 4.53 (m, 2 H, CH₂), 3.64 (m, 2 H, CH₂), 2.30 (s, 3 H,CH₃), 1.64 (s, 3 H, CH₃).

[0733] MS m/z 487 [M⁺+1].

Example 244-(4-Chloro-phenyl)-3-[3-((S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0734]

[0735] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product4-(4-Chloro-phenyl)-3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (60.1mg, 51%).

[0736]¹ H-NMR (400 MHz, DMSO-d,) δ 13.71 (br d, 1 H, pyrrole NH), 11.13(br s, 1 H,CONH), 7.47 (m, 2 H, aromatic), 7.40 (m, 2 H, aromatic), 7.27(d, 1 H, aromatic), 7.20 (t, 1 H, aromatic), 6.93 (d, 1 H, aromatic),6.74 (m, 1 H, aromatic), 6.20 (m, 1 H, aromatic), 3.30 (m, 4 H, 4×CH),3.00 (m, 1 H, CH), 2.60 (m, 1 H, CH), 2.33 (s, 3 H, CH₃), 2.21 (s, 3 H,CH₃), 2.08 (s, 3 H, CH₃), 1.64 (m, 1 H, CH).

[0737] MS m/z 475 [M⁺+1].

Example 254-(4-Chloro-phenyl)-3-[3-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0738]

[0739] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product4-(4-chloro-phenyl)-3-[3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (44.8,38%).

[0740]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.72 (br d, 1 H, pyrrole NH), 11.13(br s, 1 H, CONH), 7.47 (m, 2 H, aromatic), 7.40 (m, 2 H, aromatic),7.26 (d, 1 H, aromatic), 7.20 (t, 1 H, aromatic), 6.92 (m, 1 H,aromatic), 6.73 (m, 1 H, aromatic), 6.22 (m, 1 H, aromatic), 3.33 (m, 4H, 4×CH), 3.00 (m, 1 H, CH), 2.60 (m, 1 H, CH), 2.33 (s, 3 H, CH₃), 2.21(s, 3 H, CH₃), 2.08 (s, 3 H, CH₃), 1.64 (m, 1 H, CH).

[0741] MS m/z 475 [M⁺+1].

Example 26 5-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1 H-pyrrole-3-carboxylic acid ethylester

[0742]

[0743] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (80.3 mg, 0.26 mmol) in ethanol(2 mL) was added piperidne (3 drops). The reaction mixture was stirredat room temperature for three days. A yellow solid product wasprecipitated out, filtered, washed by ethanol for three times, and driedunder high vacuum to provide pure product5-[4-(4-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperzin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester as a yellow solid (38.8 mg,28%).

[0744]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.88 (br s, 1 H, pyrrole NH), 11.17(br s, 1 H, CONH), 7.60 (m, 2 H, aromatic), 7.50 (m, 2 H, aromatic),7.22 (t, 1 H, aromatic), 6.94 (m, 2 H, aromatic), 6.77 (d, 1 H,aromatic), 4.17 (q, 2 H, OCH₂), 3.30 (s, 1 H, CH₃) 2.25 (m, 1OH, 5×CH₂),2.11 (s, 3 H, CH₃), 2.06 (m, 2 H, CH₂), 1.26 (m, 5 H, CH_(c+CH) ₃).

[0745] MS m/z 547 [M⁺+1].

Example 274-(4-Chloro-phenyl)-3-[3-(cis)-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0746]

[0747] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and3-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product3-[3-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (22.1 mg, 19%).

[0748]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.70 (br s, 1 H, pyrrole NH), 11.13(br s, 1 H, CONH), 7.47 (m, 2 H, aromatic), 7.40 (m, 2 H, aromatic),7.20 (t, 1 H, aromatic), 7.08 (s, 1 H, aromatic), 6.93 (m, 1 H,aromatic), 6.73 (d, 1 H, aromatic), 6.07 (m, 1 H, aromatic), 4.20 (m, 1H, CH), 3.43 (m, 2 H, CH₂), 2.33 (m, 5 H, CH₂+CH₃), 2.05 (m, 1 H, CH),1.04 (m, 3 H, CH₃), 0.80 (m, 3 H, CH₃).

[0749] MS m/z 475 [M⁺+1].

Example 284-(3-Chloro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0750]

[0751] To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (61 mg, 51%)

[0752]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.45 (br s, 1 H, pyrrole NH), 11.06(br s, 1 H, CONH), 7.57 (m, 2 H, aromatic), 7.53 (m, 1 H, aromatic),7.20 (t, 1 H, aromatic), 6.95 (d, 1 H, aromatic), 6.80 (d, 1 H,aromatic), 6.77 (s, 1 H, aromatic), 3.30 (m, 4 H, 2×CH₂), 2.24 (m, 7 H,2×CH₂+CH₃), 2.17 (s, 3 H, CH₃), 1.61 (s, 3 H, CH₃).

[0753] MS m/z 475 [M⁺+1].

Example 295-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0754]

[0755] To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 to providepure product5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (73 mg, 59%)

[0756]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.51 (br s, 1 H, pyrrole NH), 11.09(br s, 1 H, CONH), 7.69 (m, 1 H, aromatic), 7.57 (m, 2 H, aromatic),7.53 (m, 1 H, aromatic), 7.41 (m, 1 H, aromatic), 7.21 (t, 1 H,aromatic), 6.96 (d, 1 H, aromatic), 6.80 (m, 2 H, aromatic), 3.22 (m, 2H, CH₂), 2.49 (m, 6 H, 3×CH₂), 2.42 (s, 3 H, CH₃), 1.76 (s, 3 H, CH₃),0.80 (t, 6 H, 2×CH₃).

[0757] MS m/z 491 [M⁺+1].

Example 305-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[0758]

[0759] To a solution of 4-(3-chloro-phenyl)- I,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-I1 H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. The reaction solution was evaporated,and purified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 toprovide pure product5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (75 mg, 61%).

[0760]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.06(br s, 1 H, CONE), 7.66 (m, 1 H, aromatic), 7.58 (m, 2 H, aromatic),7.52 (s, 1 H, aromatic), 7.47 (t, I1 H, CONH), 7.04 (m, 2 H, aromatic),7.20 (t, 1 H, aromatic), 6.95 (d, 1 H, aromatic), 6.80 (d, 1 H,aromatic), 6.78 (s, 1 H, aromatic), 3.30 (m, 2 H, CH₂), 2.50 (m, 2 H,CH₂), 2.45 (m, 4 H, 2×CH₂), 2.38 (s, 3 H, CH₃), 1.74 (s, 3 H, CH₃), 1.67(m, 4 H 2×CH₂)

[0761] MS m/z 489 [M⁺+1].

Example 315-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[0762]

[0763] To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol(2 mL) was added piperidine (3 drops). The reaction mixture was stirredat room temperature for three days. A yellow solid product wasprecipitated out, filtered, washed by ethanol for three times, and driedunder high vacuum to provide pure product5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (54 mg, 44%).

[0764]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.07(br s, 1 H, CONH), 8.10 (m, 1 H, aromatic), 7.72 (s, 1 H, aromatic),7.64 (t, 1 H, CONH), 7.58 (m, 2 H, aromatic), 7.52 (m, 1 H, aromatic),7.41 (m, 1 H, aromatic), 7.20 (t, 1 H, aromatic), 6.94 (d, 1 H,aromatic), 6.80 (d, 1 H, aromatic), 6.77 (s, 1 H, aromatic), 4.53 (m, 2H, CH₂), 3.64 (m, 2 H, CH₂), 2.29 (s, 3 H, CH₃), 1.66 (s, 3 H, CH₃).

[0765] MS m/z 487 [M⁺+1].

Example 324-(3-Chloro-phenyl)-3-[3-((S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0766]

[0767] To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product4-(3-Chloro-phenyl)-3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (70mg, 59%).

[0768]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.64 (br d, 1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 7.50 (m, 2 H, aromatic), 7.41 (s, 1 H, aromatic),7.36 (m, 1 H, aromatic), 7.21 (m, 2 H, aromatic), 6.94 (d, 1 H,aromatic), 6.78 (d, 1 H, aromatic), 6.21 (m, 1 H, aromatic), 3.54, 3.26(2×m, 1 H, CH), 3.39 (m, 2 H, CH₂), 3.04 (m, 1 H, CH), 2.60 (m, 1 H,CH), 2.33 (s, 3 H, CH₃), 2.23 (s, 3 H, CH₃), 2.08 (s, 3 H, CH₃), 1.96(m, 1 H, CH), 1.63 (m, 1 H, CH).

[0769] MS m/z 475 [M⁺+1].

Example 334-(3-Chloro-phenyl)-3-[3-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0770]

[0771] To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product4-(3-chloro-phenyl)-3-[3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (71mg, 60%).

[0772]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.63 (br m, 1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 7.45 (m, 2 H, aromatic), 7.41 (s, 1 H, aromatic),7.36 (m, 1 H, aromatic), 7.21 (m, 2 H, aromatic), 6.94 (d, 1 H,aromatic), 6.78 (d, 1 H, aromatic), 6.21 (m, 1 H, aromatic), 3.54, 3.26(2×m, 1 H, CH), 3.39 (m, 2 H, CH₂), 3.04 (m, 1 H, CH), 2.60 (m, 1 H,CH), 2.33 (s, 3 H, CH₃), 2.23 (s, 3 H, CH₃), 2.08 (s, 3 H, CH₃), 1.96(m, 1 H, CH), 1.63 (m, 1 H, CH).

[0773] MS m/z 475 [M⁺+1].

Example 342-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- [1,2,3]triazol-1-yl-ethyl)-amide

[0774]

[0775] To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 2-formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product2-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (64 mg, 54%).

[0776]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.82 (br s, 1 H, pyrrole NH), 11.14(br s, 1 H, CONH), 8.02 (m, 3 H, aromatic), 7.74 (s, 1 H, aromatic),7.46 (m, 2 H, aromatic), 7.40 (m, 1 H, aromatic), 7.33 (m, 1 H,aromatic), 7.22 (t, 1 H, aromatic), 6.94 (d, 1 H, aromatic), 6.78 (d, 1H, aromatic), 6.34 (m, 1 H, aromatic), 4.51 (m, 2 H, CH₂), 3.50 (m, 2 H,CH₂), 2.31 (s, 3 H, CH₃).

[0777] MS m/z 473 [M⁺+1].

Example 354-(3-Chloro-phenyl)-3-[3-((cis)-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0778]

[0779] To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and3-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95to providepure product 3-[3-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (67 mg, 56%).

[0780]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.60 (br s, 1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 7.45 (m, 2 H, aromatic), 7.40 (s, 1 H, aromatic),7.33 (m, 1 H, aromatic), 7.20 (t, 1 H, aromatic), 6.94 (m, 2 H,aromatic), 6.77 (d, 1 H, aromatic), 6.06 (m, 1 H, aromatic), 4.13 (m, 1H, CH), 3.32 (m, 1 H, CH), 2.39 (m, 6 H, CH+CH₂+CH₃), 2.05 (m, 1 H, CH),1.04 (m, 3 H, CH₃), 0.80 (m, 3 H, CH₃). MS m/z475 [M⁺+1].

Example 36 3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]4-(4-methoxy-phenyl)- I,3-dihydro-indol-2-one

[0781]

[0782] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one asa yellow solid (85 mg, 72%)

[0783]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.42 (br s, 1 H, pyrrole NH), 10.98(br s, 1 H, CONH), 7.30 (m, 2 H, aromatic), 7.15 (t, 1 H, aromatic),7.10 (m, 2 H, aromatic), 6.89 (d, 1 H, aromatic), 6.76 (m, 2 H,aromatic), 3.80 (s, 3 H, OCH₃), 3.31 (m, 4 H, 2×CH₂), 2.22 (m, 7 H,2×CH₂+CH₃), 2.15 (s, 3 H, CH₃), 1.60 (s, 3 H, CH₃).

[0784] MS m/z 471 [M⁺+1].

Example 37 5-[4-(4-Methoxy-phenyl)2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0785]

[0786] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide (69.0 mg, 0.25 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (87 mg, 72%).

[0787]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.44 (br s, 1 H, pyrrole NH), 10.98(br s, 1 H, CONH), 7.31 (m, 3 H; aromatic), 7.16 (t, 1 H, aromatic),7.11 (m, 2 H, aromatic), 6.90 (m, 1 H, aromatic), 6.78 (m, 2 H,aromatic), 3.82 (s, 3 H, OCH₃), 3.22 (m, 2 H, CH₂), 2.49 (m, 6 H,3×CH₂), 2.39 (s, 3 H, CH₃), 1.73 (s, 3 H, CH₃), 0.95 (t, 6 H, 2×CH₃).106221 MS m/z 487 [M⁺+1].

Example 385-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[0788]

[0789] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.25 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product5-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1IH-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (86 mg, 71%).

[0790]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.46 (br s, 1 H, pyrrole NH), 10.99(br s, 1 H, CONH), 7.41 (m, 1 H, CONH), 7.32 (m, 2 H, aromatic), 7.16(t, 1 H, aromatic), 7.11 (m, 2 H, aromatic), 6.90 (m, 1 H, aromatic),6.78 (m, 2 H, aromatic), 3.82 (s, 3 H, OCH₃), 3.28 (m, 2 H, CH₂), 2.50(m, 2 H, CH₂), 2.46 (m, 4 H, 2×CH₂), 2.37 (s, 3 H, CH₃), 1.73 (s, 3 H,CH₃), 1.67 (m, 4 H 2×CH₂).

[0791] MS m/z 485 [M⁺+1].

Example 395-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[0792]

[0793] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.25 mmol) in ethanol(2 mL) was added piperidine (3 drops). The reaction mixture was stirredat room temperature for three days. A yellow solid product wasprecipitated out, filtered, washed by ethanol for three times, and driedunder high vacuum to provide pure product5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (54 mg, 45%). 106271 ¹ H-NMR (400 MHz, DMSO-d₆) δ 13.47 (brs, 1 H, pyrrole NH), 11.00 (br s, 1 H, CONH), 8.10 (m, 1 H, aromatic),7.71 (m, 1 H, aromatic), 7.60 (m, 1 H, CONH), 7.31 (m, 2 H, aromatic),7.16 (t, 1 H, aromatic), 7.10 (m, 2 H, aromatic), 6.89 (m, 1 H,aromatic), 6.78 (m, 2 H, aromatic), 4.53 (m, 2 H, CH₂), 3.82 (s, 3 H,OCH₃), 3.63 (m, 2 H, CH₂), 2.29 (s, 3 H, CH₃), 1.61 (s, 3 H, CH₃).

[0794] MS m/z 483 [M⁺+1].

Example 403-[4-((cis)-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one

[0795]

[0796] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product3-[4-[(cis)-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one asa yellow solid (88 mg, 73%).

[0797]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.40 (br s, 1 H, pyrrole NH), 10.99(br s, 1 H, CONH), 7.33 (m, 2 H, aromatic), 7.16 (t, 1 H, aromatic),7.10 (m, 2 H, aromatic), 6.90 (m, 1 H, aromatic), 6.77 (m, 2 H,aromatic), 3.80 (s, 3 H, OCH₃), 3.43 (m, 1 H, CH), 2.52 (m, 1 H, CH),2.23 (m, 4 H, 2×CH₂), 1.57 (m, 3 H, CH₃), 1.04 (m, 3 H, CH₃), 0.90 (m, 6H, 2×CH₃).

[0798] MS m/z 485 [M⁺+1].

Example 412-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[0799]

[0800] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product2-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (90 mg, 77%).

[0801]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.73 (br s, 1 H, pyrrole NH), 11.05(br s, 1 H, CONH), 7.99 (s, 1 H, aromatic), 7.67 (t, 1 H, CONH), 7.26(m, 2 H, aromatic), 7.17 (t, 1 H, aromatic), 6.98 (m, 2 H, aromatic),6.87 (m, 1 H, aromatic), 6.74 (m, 1 H, aromatic), 6.35 (m, 1 H,aromatic), 3.81 (s, 3 H, OCH₃), 3.13 (m, 2 H, CH₂), 2.46 (m, 6 H,3×CH₂), 2.31 (s, 3 H, CH₃), 1.68 (m, 4 H 2×CH₂).

[0802] MS m/z 471 [M⁺+1].

Example 422-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[0803]

[0804] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product2-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (61 mg, 52%).

[0805]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.84 (br s, 1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 7.98 (m, 3 H, aromatic), 7.73 (s, 1 H, aromatic),7.27 (m, 2 H, aromatic), 7.18 (t, 1 H, aromatic), 6.99 (m, 2 H,aromatic), 6.88 (m, 1 H, aromatic), 6.75 (m, 1 H, aromatic), 6.30 (m, 1H, aromatic), 4.47 (t, 2 H, CH₂), 3.75 (m, 3 H, OCH₃), 3.45 (m, 2 H,CH₂), 2.30 (s, 3 H, CH₃).

[0806] MS m/z 469 [M⁺+1].

Example 43 3-[3-((3S)-3-Dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one

[0807]

[0808] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and3-[(3S)-3-Dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one asa yellow solid (94 mg, 80%).

[0809]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.69 (br m, 1 H, pyrrole NH), 11.10(br s, ;1 H, CONH), 7.29 (m, 2 H, aromatic), 7.18 (m, 2 H, aromatic),6.98 (m, 2 H, aromatic), 6.88 (d, 1 H, aromatic), 6.73 (d, 1 H,aromatic), 6.15 (s, 1 H, aromatic), 3.84 (m, 3 H, OCH₃), 3.32 (m, 1 H,CH), 3.00 (4×m, 2 H, 2×CH), 2.60 (m, 1 H, CH), 2.55, 2.00 (4×m, 2 H,2×CH), 2.33 (m, 3 H, CH₃), 2.19 (s, 3 H, CH₃), 2.05 (s, 3 H, CH₃), 1.64(m, 1 H, CH).

[0810] MS m/z 471 [M⁺+1].

Example 44 3-[3-((R)-3-Dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one

[0811]

[0812] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and3-[(3R)-3-Dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product3-[3-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one asa yellow solid (95 mg, 81%).

[0813]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.69 (br d, 1 H, pyrrole NH), 11.10(br s, 1 H, CONH), 7.29 (m, 2 H, aromatic), 7.18 (m, 2 H, aromatic),6.98 (m, 2 H, aromatic), 6.88 (d, 1 H, aromatic), 6.73 (d, 1 H,aromatic), 6.15 (s, 1 H, aromatic), 3.84 (m, 3 H, OCH₃), 3.32 (m, 1 H,CH), 3.00 (4×m, 2 H, 2×CH), 2.52 (m, 1 H, CH), 2.55 (m, 1 H, CH), 2.00,1.90 (2×m, 1 H, CH), 2.32 (m, 3 H, CH₃), 2.20 (s, 3 H, CH₃), 2.05 (s, 3H, CH₃), 1.64 (m, 1 H, CH).

[0814] MS m/z 471 [M⁺+1].

Example 45 3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one

[0815]

[0816] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 to provide3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-I,3-dihydro-indol-2-one asa yellow solid (62 mg, 53%)

[0817]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.45 (br s, 1 H, pyrrole NH), 11.02(br s, 1 H, CONH), 7.46 (t, 1 H, aromatic), 7.18 (t, 1 H, aromatic),7.04 (m, 1 H, aromatic), 6.97 (m, 2 H, aromatic), 6.92 (d, 1 H,aromatic), 6.83 (s, 1 H, aromatic), 6.80 (d, 1 H, aromatic), 3.77 (s, 3H, OCH₃), 3.30 (m, 4 H, 2×CH₂), 2.24 (m, 7 H, 2×CH₂+CH₃), 2.17 (s, 3 H,CH₃), 1.58 (s, 3 H, CH₃).

[0818] MS m/z 471 [M⁺+1].

Example 465-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide

[0819]

[0820] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide (69.0 mg, 0.25 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 to provide5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (94 mg, 78%).

[0821]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.02(br s, 1 H, CONE), 7.47 (t, 1 H, aromatic), 7.35 (t, 1 H, CONH), 7.19(t, 1 H, aromatic), 7.06 (m, 1 H, aromatic), 6.98 (m, 2 H, aromatic),6.92 (d, 1 H, aromatic), 6.88 (s, 1 H, aromatic), 6.80 (d, 1 H,aromatic), 3.77 (s, 1 H, CH₃), 3.25 (m, 2 H, CH₂), 2.38 (s, 3 H, CH₃),2.50 (m, 6 H, 3×CH₂), 1.73 (s, 3 H, CH₃), 0.95 (t, 6 H, 2×CH₃).

[0822] MS m/z 487 [M⁺+1].

Example 475-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[0823]

[0824] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.25 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. The reaction solution was evaporated,and purified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 toprovide pure product5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (97 mg, 80%).

[0825]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.01(br s, 1 H, CONH), 7.50 (m, 2 H, aromatic), 7.17 (t, 1 H, aromatic),7.11 (m, 1 H, aromatic), 6.97 (m, 2 H, aromatic), 6.92 (d, 1 H,aromatic), 6.87 (s, 1 H, aromatic), 6.80 (d, 1 H, aromatic), 3.78 (s, 3H, OCH₃), 3.30 (m, 2 H, CH₂), 2.50 (m, 6 H, 3×CH₂), 2.37 (s, 3 H, CH₃),1.70 (s, 3 H, CH₃), 1.68 (m, 4 H 2×CH₂).

[0826] MS m/z 485 [M⁺+1].

Example 485-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[0827]

[0828] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.25 mmol) in ethanol(2 mL) was added piperidine (3 drops). The reaction mixture was stirredat room temperature for three days. A yellow solid product wasprecipitated out, filtered, washed by ethanol for three times, and driedunder high vacuum to provide pure product5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[l,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (18 mg, 15%). 106541 ¹ H-NMR (400 MHz, DMSO-d₆) δ 13.47 (brs, 1 H, pyrrole NH), 11.02 (br s, 1 H, CONH), 8.10 (s, 1 H, aromatic),7.71 (s, 1 H, aromatic), 7.62 (t, 1 H, CONH), 7.46 (t, 1 H, aromatic),7.16 (t, 1 HI, aromatic), 7.07 (m, 1 H, aromatic), 6.97 (m, 2 H,aromatic), 6.95 (d, 1 H, aromatic), 6.84 (s, 1 H, aromatic), 6.80 (d, 1H, aromatic), 4.53 (m, 2 H, CH₂), 3.78 (s, 3 H, OCH₃), 3.63 (m, 2 H,CH₂), 2.29 (s, 3 H, CH₃), 1.61 (s, 3 H, CH₃).

[0829] MS m/z 483 [M⁺+1].

Example 493-[4-((cis)-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one

[0830]

[0831] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 to providepure product3-[4-((cis)-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one asa yellow solid (95 mg, 79%).

[0832]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.40 (br s, 1 H, pyrrole NH), 11.00(br s, 1 H, CONH), 7.46 (t, 1 H, aromatic), 7.17 (t, 1 H, aromatic),7.05 (m, 1 H, aromatic), 6.98 (m, 2 H, aromatic), 6.92 (d, 1 H,aromatic), 6.85 (s, 1 H, aromatic), 6.80 (d, 1 H, aromatic), 3.80 (s, 3H, OCH₃), 3.43 (m, 1 H, CH), 2.52 (m, 1 H, CH), 2.23 (m, 4 H, 2×CH₂),1.57 (m, 3 H, CH₃), 1.04 (m, 3 H, CH₃), 0.90 (m, 6 H, 2×CH₃).

[0833] MS m/z 485 [M⁺+1].

Example 502-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[0834]

[0835] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product2-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (40 mg, 34%).

[0836]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.80 (br s, 1 H, pyrrole NH), 11.09(br s, 1 H, CONH), 8.03 (s, 1 H, aromatic), 7.71 (t, 1 H, CONH), 7.32(m, 1 H, aromatic), 7.28 (t, 1 H, aromatic), 6.90 (m, 4 H, aromatic),6.78 (d, 1 H, aromatic), 6.35 (m, 1 H, aromatic), 3.74 (s, 3 H, OCH₃),3.14 (m, 2 H, CH₂), 2.50 (m, 6 H, 3×CH₂), 2.32 (s, 3 H, CH₃), 1.69 (m, 4H 2×CH₂).

[0837] MS m/z 471 [M⁺+1].

Example 512-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[0838]

[0839] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product2-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]-triazol-1-yl-ethyl)-amide as ayellow solid (51 mg, 43%).

[0840]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.86 (br s, 1 H, pyrrole NH), 11.02(br s, 1 H), 8.00 (m, 3 H, aromatic), 7.72 (s, 1 H, aromatic), 7.65 (t,1 H, aromatic), 7.39 (t, 1 H, aromatic), 6.92 (m, 4 H, aromatic), 6.79(d, 1 H, aromatic), 6.30 (m, 1 H, aromatic), 4.49 (t, 2 H, CH₂), 3.76(s, 3 H, OCH₃), 3.47 (m, 2 H, CH₂), 2.29 (s, 3 H, CH₃).

[0841] MS m/z 469 [M⁺+1].

Example 525-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide

[0842]

[0843] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-diisopropylamino-ethyl)-amide (73 mg, 0.25 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. The reaction solution was evaporated,and purified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 toprovide pure product5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide as a yellowsolid (95 mg, 79%).

[0844]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1 H, pyrrole NH), 11.03(br s, 1 H, CONH), 7.47 (m, 1 H, aromatic), 7.33 (m, 1 H, aromatic),7.17 (t, 1 H, aromatic), 7.06 (m, 1 H, aromatic), 6.98 (m, 2 H,aromatic), 6.92 (d, 1 H, aromatic), 6.88 (s, 1 H, aromatic), 6.80 (d, 1H, aromatic), 3.77 (s, 1 H, CH₃), 3.31 (m, 2 H, CH₂), 3.29 (m, 2 H,CH₂), 2.39 (s, 3 H, CH₃),l.73 (m, 3 H, CH₃), 0.99 (m, 12 H, 4×CH₃).

[0845] MS m/z 515 [M⁺+1].

Example 534-(4-Bromo-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0846]

[0847] To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine- l -carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide4-(4-bromo-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (38mg, 29%)

[0848]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.41 (br s, 1 H, pyrrole NH), 11.04(br s, 1 H, CONH), 7.75 (d, 2 H, aromatic), 7.395 (d, 2 H, aromatic),7.19 (t, 1 H, aromatic), 6.93 (d, 1 H, aromatic), 6.79 (d, 1 H,aromatic), 6.64 (s, 1 H, aromatic), 3.31 (m, 4 H, 2×CH₂), 2.25 (m, 7 H,2×CH₂+CH₃), 2.17 (s, 3 H, CH₃), 1.61 (s, 3 H, CH₃).

[0849] MS m/z 519 [M⁺+1].

Example 545-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihvdro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole3-carboxylic acid (2-diethylamino-ethyl)-amide

[0850]

[0851] To a solution of 4- (4-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg,0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide as a yellow solid (59 mg, 44%)

[0852]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.44 (br s, 1 H, pyrrole NH), 11.04(br s, 1 H, CONH), 7.74 (d, 2 H, aromatic), 7.37 (d, 2 H, aromatic),7.33 (t, 1 H, CONH), 7.19 (t, 1 H, aromatic), 6.93 (d, 1 H, aromatic),6.80 (m, 1 H, aromatic), 6.66 (s, 1 H, aromatic), 3.24 (m, 2 H, CH₂),2.49 (m, 6 H, 3×CH₂), 2.39 (s, 3 H, CH₃), 1.75 (s, 3 H, CH₃), 0.96 (t, 6H, 2×CH₃).

[0853] MS m/z 535 [M⁺+1].

Example 555-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[0854]

[0855] To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (63 mg, 47%).

[0856]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.43 (br s, 1 H, pyrrole NH), 11.04(br s, 1 H, CONH), 7.74 (m, 2 H, aromatic), 7.42 (t, 1 H, CONH), 7.36(d, 2 H, aromatic), 7.19 (t, 1 H, aromatic), 6.95 (d, 1 H, aromatic),6.79 (m, 1 H, aromatic), 6.65 (s, 1 H, aromatic), 3.30 (m, 2 H, CH₂),2.50 (m, 2 H, CH₂), 2.46 (m, 4 H, 2×CH₂), 2.37 (s, 3 H, CH₃), 1.73 (s, 3H, CH₃), 1.67 (m, 4 H 2×CH₂).

[0857] MS m/z 533 [M⁺+1].

Example 565-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[ 1,2,3]triazol-1-yl-ethyl)-amide

[0858]

[0859] To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (50 mg, 38%).

[0860]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.43 (br s, 1 H, pyrrole NH), 11.05(br s, 1 H, CONH), 8.10 (s, 1 H, aromatic), 7.72 (m, 3 H, aromatic),7.62 (t, 1 H, CONH), 7.47 (d, 2 H, aromatic), 7.19 (t, 1 H, aromatic),6.93 (d, 1 H, aromatic), 6.78 (d, 1 H, aromatic), 6.63 (s, 1 H,aromatic), 4.53 (m, 2 H, CH₂), 3.64 (m, 2 H, CH₂), 2.30 (s, 3 H, CH₃),1.64 (s, 3 H, CH₃).

[0861] MS m/z 531 [M⁺+1].

Example 574-(4-Bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0862]

[0863] To a solution of 4-(4-bromo-phenyl)-I,3-dihydro-indol-2-one (72mg, 0.25 mmol) and4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product4-(4-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (38mg, 28%).

[0864]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.40 (br m, 1 H, pyrrole NH), 11.03(br s, 1 H, CONH), 7.74 (d, 2 H, aromatic), 7.39 (d, 2 H, aromatic),7.19 (t, 1 H, aromatic), 6.93 (d, 1 H, aromatic), 6.79 (d, 1 H,aromatic), 6.62 (s, 1 H, aromatic), 4.20 (m, 1 H, NH), 3.43 (m, 4 H,2×CH₂), 2.52 (m, 2 H, 2×CH), 2.23 (m, 3 H, CH₃), 1.59 (m, 3 H, CH₃),0.90 (m, 6 H, 2×CH₃).

[0865] MS m/z 533 [M⁺+1].

Example 582-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[0866]

[0867] To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 2-formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product2-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (78 mg, 60%).

[0868]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.73 (br s, 1 H, pyrrole NH), 11.05(br s, 1 H, CONH), 8.05 (s, 1 H, aromatic), 7.72 (t, 1 H, CONH), 7.58(d, 2 H, aromatic), 7.30 (d, 2 H, aromatic), 7.19 (t, 1 H, aromatic),6.93 (d, 1 H, aromatic), 6.75 (d, 1 H, aromatic), 6.41 (s, 1 H,aromatic), 3.30 (m, 2 H, CH₂), 2.50 (m, 6 H, 3×CH₂), 2.31 (s, 3 H, CH₃),1.67 (m, 4 H 2×CH₂).

[0869] MS m/z 519 [M⁺+1].

Example 592-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2- [1,2,3]triazol-1-yl-ethyl)-amide

[0870]

[0871] To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 2-formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product2-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (88 mg, 68%).

[0872]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.84 (br s, 1 H, pyrrole NH), 11.13(br s, 1 H, CONH), 8.00 (m, 3 H, aromatic), 7.73 (s, 1 H, aromatic),7.63 (m, 2 H, aromatic), 7.32 (d, 2 H, aromatic), 7.21 (t, 1 H,aromatic), 6.93 (d, 1 H, aromatic), 6.76 (d, 1 H, aromatic), 6.33 (m, 1H, aromatic), 4.53 (m, 2 H, CH₂), 3.54 (m, 2 H, CH₂), 2.29 (s, 3 H,CH₃).

[0873] MS m/z 517 [M +1].

Example 605-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole3-carboxylic acid (2-diisopropylamino-ethyl)-amide

[0874]

[0875] To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid(2-diisopropylamino-ethyl)-amide (73 mg, 0.25 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide as a yellowsolid (40 mg, 28%).

[0876]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.44 (br s, 1 H, pyrrole NH), 11.04(br s, 1 H, CONH), 7.74 (d, 2 H, aromatic), 7.38 (d, 2 H, aromatic),7.29 (t, 1 H, CONE), 7.19 (t, 1 H, aromatic), 6.93 (d, 1 H, aromatic),6.80 (d, 1 H, aromatic), 6.72 (s, 1 H, aromatic), 3.31 (m, 2 H, CH₂),3.29 2.50 (m, 2 H, 2×CH), (m, 2 H, CH₂), 2.39 (s, 3 H, CH₃),1.73 (m, 3H, CH₃), 0.99 (m, 12 H, 4×CH₃).

[0877] MS m/z 563 [M⁺+1].

Example 615-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0878]

[0879] To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (62.8 mg, 0.25 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (82 mg, 63%).

[0880]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.41 (br s, 1 H, pyrrole NH), 11.10(br s, 1 H, CONH), 7.75 (d, 2 H, aromatic), 7.66 (m, 2 H, aromatic),7.39 (d, 2 H, aromatic), 7.21 (t, 1 H, aromatic), 6.93 (d, 1 H,aromatic), 6.81 (m, 1 H, aromatic), 6.73 (s, 1 H, aromatic), 3.20 (m, 2H, CH₂), 2.49 (m, 6 H, 3×CH₂), 1.74 (s, 3 H, CH₃), 0.95 (t, 6 H, 2×CH₃).

[0881] MS m/z 521 [M++I].

Example 624-(3-Bromo-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0882]

[0883] To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide4-(3-bromo-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (48mg, 37%)

[0884]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.45 (br s, 1 H, pyrrole NH), 11.06(br s, 1 H, CONH), 7.69 (d, 1 H, aromatic), 7.65 (s, 1 H, aromatic),7.52 (t, 1 H, aromatic), 7.45 (d, 1 H, aromatic), 7.20 (t, 1 H,aromatic), 6.94 (d, 1 H, aromatic), 6.81 (d, 1 H, aromatic), 6.76 (s, 1H, aromatic), 3.33 (m, 4 H, 2×CH₂), 2.24 (m, 7 H, 2×CH₂+CH₃), 2.17 (s, 3H, CH₃), 1.62 (s, 3 H, CH₃).

[0885] MS m/z 519 [M⁺+1].

Example 635-l4-(3-Bromophenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0886]

[0887] To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (89.7 mg, 67%)

[0888]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.06(br s, 1 H, CONH), 7.71 (d, 1 H, aromatic), 7.65 (s, 1 H, aromatic),7.53 (t, 1 H, aromatic), 7.44 (d, 1 H, aromatic), 7.37 (t, 1 H, CONH),7.20 (t, 1 H, aromatic), 6.94 (d, 1 H, aromatic), 6.80 (d, 1 H,aromatic), 6.78 (s, 1 H, aromatic), 3.23 (m, 2 H, CH₂), 2.49 (m, 6 H,3×CH₂), 2.39 (s, 3 H, CH₃), 1.76 (s, 3 H, CH₃), 0.95 (t, 6 H, 2×CH₃).

[0889] MS m/z 535 [M⁺+1].

Example 645-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[0890]

[0891] To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 to providepure product5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (84 mg, 63%)

[0892]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.06(br s, 1 H, CONH), 7.71 (d, 1 H, aromatic), 7.65 (s, 1 H, aromatic),7.52 (t, 1 H, aromatic), 7.45 (m, 2 H, CONH and aromatic), 7.20 (t, 1 H,aromatic), 6.95 (d, 1 H, aromatic), 6.80 (d, 1 H, aromatic), 6.78 (s, 1H, aromatic), 3.30 (m, 2 H, CH₂), 2.52 (m, 6 H, 3×CH₂), 2.37 (s, 3 H,CH₃), 1.74 (s, 3 H, CH₃), 1.68 (m, 4 H 2×CH₂).

[0893] MS m/z 531 [M⁻−1].

Example 655-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[0894]

[0895] To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (46.6 mg, 35%).

[0896]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.07(br s, 1 H, CONH), 8.10 (s, 1 H, aromatic), 7.72 (m, 2 H, aromatic),7.65 (m, 2 H, aromatic), 7.52 (t, 1 H, CONH), 7.42 (d, 1 H, aromatic),7.20 (t, 1 H, aromatic), 6.94 (d, 1 H, aromatic), 6.80 (d, 1 H,aromatic), 6.76 (s, 1 H, aromatic), 4.53 (m, 2 H, CH₂), 3.64 (m, 2 H,CH₂), 2.26 (s, 3 H, CH₃), 1.67 (s, 3 H, CH₃).

[0897] MS m/z 531 [M⁺+1].

Example 664-(3-Bromo-phenyl)-3-[4-(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[0898]

[0899] To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 to providepure product4-(3-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (95mg, 70%).

[0900]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.43 (br m, 1 H, pyrrole NH), 11.06(br s, 1 H, CONH), 7.70 (d, 1 H, aromatic), 7.65 (s, 1 H, aromatic),7.52 (t, 1 H, aromatic), 7.45 (d, 1 H, aromatic), 7.20 (t, 1 H,aromatic), 6.94 (d, 1 H, aromatic), 6.80 (d, 1 H, aromatic), 6.76 (s, 1H, aromatic), 3.30 (m, 4 H, 2×CH₂), 2.54 (m, 2 H, 2×CH), 2.30 (br s, 1H, NH), 2.23 (s, 3 H, CH₃), 1.61 (s, 3 H, CH₃), 0.93 (m, 6 H, 2×CH₃).

[0901] MS m/z 531 [M⁻−1].

Example 672-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[0902]

[0903] To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 2-formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product2-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (93 mg, 72%).

[0904]¹ H-NMR(400 MHz, DMSO-d₆) δ 13.80 (br s, 1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 8.02 (s, 1 H, aromatic), 7.77 (t, 1 H, CONH), 7.52(m, 2 H, aromatic), 7.38 (m, 2 H, aromatic), 7.21 (t, 1 H, aromatic),6.93 (d, 1 H, aromatic), 6.77 (d, 1 H, aromatic), 6.39 (s, 1 H,aromatic), 3.18 (dd, 2 H, CH₂), 2.48 (m, 6 H, 3×CH₂), 2.32 (s, 3 H,CH₃), 1.70 (m, 4 H, 2×CH₂).

[0905] MS m/z 5l9 [M⁺+1].

Example 682-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[0906]

[0907] To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 2-formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product2-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (96 mg, 74%).

[0908]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.82 (br s, 1 H, pyrrole NH), 11.14(br s, 1 H, CONH), 8.03 (t, 1 H, CONH), 8.00 (s, 2 H, aromatic), 7.74(s, 1 H, aromatic), 7.61 (m, 1 H, aromatic), 7.53 (m, 1 H, aromatic),7.41 (t, 1 H, aromatic), 7.35 (m, 1 H, aromatic), 7.21 (t, 1 H,aromatic), 6.94 (d, 1 H, aromatic), 6.78 (d, 1 H, aromatic), 6.34 (d, 1H, aromatic), 4.52 (m, 2 H, CH₂), 3.51 (m, 2 H, CH₂), 2.31 (s, 3 H,CH₃).

[0909] MS m/z 517 [M⁺+1].

Example 695-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole3-carboxylic acid (2-diisopropylamino-ethyl)-amide

[0910]

[0911] To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid(2-diisopropylamino-ehtyl)-amide (73 mg, 0.25 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pylamino-ethyl)-amide as a yellow solid(43 mg, 30%).

[0912]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.50 (br s, 1 H, pyrrole NH), 11.06(br s, 1 H, CONH), 7.71 (d, 1 H, aromatic), 7.66 (s, 1 H, aromatic),7.52 (t, 1 H, aromatic), 7.44 (d, 1 H, aromatic), 7.34 (t, 1 H, CONH),7.20 (t, 1 H, aromatic), 6.94 (d, 1 H, aromatic), 6.80 (d, 1 H,aromatic), 6.78 (s, 1 H, aromatic), 3.13 (m, 2 H, CH₂), 2.97 (m, 2 H,2×H), 2.50 (m, 2 H, CH₂), 2.40 (s, 3 H, CH₃),1.76 (s, 3 H, CH₃), 0.97(d, 12 H, 4×CH₃).

[0913] MS m/z 563 [M⁺+1].

Example 705-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide

[0914]

[0915] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-2-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 to providepure product5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (52 mg, 45%).

[0916]¹ H-NMR (400 MHz, DMSO-d₆) 313.51 (br s,1 H, pyrrole NH), 11.10(br s, 1 H, CONH), 8.26 (t, 1 H, CONH), 7.48 (m, 2 H, aromatic), 7.39(m, 2 H, aromatic), 7.23 (t, 1 H, aromatic), 6.94 (d, 1 H, aromatic),6.80 (d, 1 H, aromatic), 6.73 (s, 1 H, aromatic), 6.68 (d, 1 H,aromatic), 3.30 (m, 2 H, CH₂), 2.50 (m, 6 H, 3×CH₂), 1.69 (s, 3 H, CH₃),0.96 (t, 6 H, 2×CH₃).

[0917] MS m/z 461 [M⁺+1].

Example 715-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide

[0918]

[0919] To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-2-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl2 5:95 to providepure product5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (26 mg, 23%).

[0920]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.55 (br s, 1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 8.30 (t, 1 H, CONH), 7.60 (dd, 1 H, aromatic), 7.33(m, 3 H, aromatic), 7.25 (t, 1 H, aromatic), 6.95 (d, 1 H, aromatic),6.83 (d, 1 H, aromatic), 6.81 (s, 1 H, aromatic), 6.69 (d, 1 H,aromatic), 3.30 (m, 2 H, CH₂), 2.50 (m, 6 H, 3×CH₂), 1.69 (s, 3 H, CH₃),0.96 (t, 6 H, 2×CH₃).

[0921] MS m/z 461 [M⁺+1].

Example 725-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide

[0922]

[0923] To a solution of 4-(4-Chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-2-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 to providepure product5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (80 mg, 67%).

[0924]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.50 (br s, 1 H, pyrrole NH), 11.10(br s, 1 H, CONH), 8.29 (br s, 1 H, CONH), 7.63 (d, 2 H, aromatic), 7.47(d, 2 H, aromatic), 7.24 (t, 1 H, aromatic), 6.94 (d, 1 H, aromatic),6.82 (d, 1 H, aromatic), 6.70 (m, 2 H, aromatic), 3.30 (m, 2 H, CH₂),2.57 (m, 6 H, 3×CH₂), 1.69 (s, 3 H, CH₃), 0.98 (t, 6 H, 2×CH₃)

[0925] MS m/z 477 [M⁺+1].

Example 735-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole2-carboxylic acid (2-diethylamino-ethyl)-amide

[0926]

[0927] To a solution of 4-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-2-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 to providepure product5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (65 mg, 54%).

[0928]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.53 (br s, 1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 8.31 (br s, 1 H, CONH), 7.58 (m, 3 H, aromatic), 7.42(m, 1 H, aromatic), 7.25 (t, 1 H, aromatic), 6.92 (d, 1 H, aromatic),6.82 (d, 1 H, aromatic), 6.80 (s, 1 H, aromatic), 6.69 (d, 1 H,aromatic), 3.30 (m, 2 H, CH₂), 2.57 (m, 6 H, 3×CH₂), 1.70 (s, 3 H, CH₃),0.98 (t, 6 H, 2×CH₃).

[0929] MS m/z 475 [M⁻−1].

Example 745-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide

[0930]

[0931] To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-2-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (26 mg, 20%).

[0932]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.10(br s, 1 H, CONH), 8.24 (t, 1 H, CONH), 7.76 (d, 2 H, aromatic), 7.38(d, 2 H, aromatic), 7.24 (t, 1 H, aromatic), 6.94 (d, 1 H, aromatic),6.81 (d, 1 H, aromatic), 6.69 (m, 2 H, aromatic), 3.26 (m, 2 H, CH₂),2.50 (m, 6 H, 3×CH₂), 1.70 (s, 3 H, CH₃), 0.95 (t, 6 H, 2×CH₃).

[0933] MS m/z 521 [M⁺+1].

Example 755-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide

[0934]

[0935] To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-2-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 to providepure product5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (45 mg, 35%).

[0936]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.52 (br s, 1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 8.27 (t, 1 H, CONH), 7.72 (d, 1 H, aromatic), 7.68(s, 1 H, aromatic), 7.53 (t, 1 H, aromatic), 7.46 (d, 1 H, aromatic),7.25 (t, 1 H, aromatic), 6.95 (d, 1 H, aromatic), 6.82 (d, 1 H,aromatic), 6.79 (s, 1 H, aromatic), 6.69 (s, 1 H, aromatic), 3.29 (m, 2H, CH₂), 2.50 (m, 6 H, 3×CH₂), 1.71 (s, 3 H, CH₃), 0.96 (t, 6 H, 2×CH₃).

[0937] MS m/z 519 [M⁻−1].

Example 765-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide.

[0938]

[0939] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-2-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (65 mg, 55%).

[0940]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.85 (br s, 1 H, pyrrole NH), 8.18(m, 1 H, CONH), 7.33 (d, 2 H, aromatic), 7.16 (t, 1 H, aromatic), 7.10(d, 2 H, aromatic), 6.86 (d, 1 H, aromatic), 6.76 (s, 1 H, aromatic),6.73 (d, 1 H, aromatic), 6.65 (s, 1 H, aromatic), 3.82 (s, 3 H, OCH₃),3.25 (m, 2 H, CH₂), 2.47 (m, 6 H, 3×CH₂), 1.67 (s, 3 H, CH₃), 0.95 (t, 6H, 2×CH₃).

[0941] MS m/z 473 [M⁺+1].

Example 775-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide

[0942]

[0943] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-2-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The reaction solution was evaporated, andpurified on a silica gel column eluting with MeOH—CH₂Cl₂ 5:95 to providepure product5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (40 mg, 34%).

[0944]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.52 (br s, 1 H, pyrrole NH), 11.07(br s, 1 H, CONH), 8.26 (m, 1 H, CONH), 7.48 (t, 1 H, aromatic), 7.22(t, 1 H, aromatic), 7.06 (dd, 1 H, aromatic), 7.00 (m, 2 H, aromatic),6.92 (d, 1 H, aromatic), 6.89 (s, 1 H, aromatic), 6.82 (d, 1 H,aromatic), 6.67 (m, 1 H, aromatic), 3.78 (s, 3 H, CH₃), 3.29 (m, 2 H,CH₂), 2.55 (m, 6 H, 3×CH₂), 1.67 (s, 3 H, CH₃), 0.97 (t, 6 H, 2×CH₃).

[0945] MS m/z 471 [M⁻−1].

Example 78 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one

[0946]

[0947] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 3,5-dimethyl-1 H-pyrrole-2-carbaldehyde (32 mg,0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). Thereaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (35 mg, 45%).

[0948]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.23 (br s, 1 H, pyrrole NH), 10.93(br s, 1 H, CONH), 7.47 (dd, 2 H, aromatic), 7.37 (t, 2 H, aromatic),7.14 (t, 1 H, aromatic), 6.91 (d, 1 H,aromatic), 6.76 (d, 1 H,aromatic), 6.68 (s, 1 H, aromatic), 5.91 (d, 1 H, aromatic), 2.27 (s, 3H, CH₃), 1.67 (s, 3 H, CH₃).

[0949] MS m/z 333 [M⁺+1].

Example 79 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[0950]

[0951] To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 3,5-dimethyl-1 H-pyrrole-2-carbaldehyde (32 mg,0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). Thereaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (37 mg, 46%).

[0952]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.24 (br s, 1 H, pyrrole NH), 10.95(br s, 1 H, CONH), 7.59 (dd, 1 H, aromatic), 7.31 (m, 3 H, aromatic),7.16 (t, 1 H, aromatic), 6.93 (d, 1 H, aromatic), 6.78 (d, 1 H,aromatic), 6.76 (s, 1 H, aromatic), 5.91 (d, 1 H, aromatic), 2.27 (s, 3H, CH₃), 1.65 (s, 3 H, CH₃).

[0953] MS m/z 333 [M⁺+1].

Example 80 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one

[0954]

[0955] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 3,5-dimethyl-1 H-pyrrole-2-carbaldehyde (32 mg,0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). Thereaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-(3,5-Dimethyl-1H-pyrrol-2-ylnethylene)-4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (36 mg, 41%).

[0956]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.21 (br s, 1 H, pyrrole NH), 10.94(br s, 1 H, CONH), 7.60 (d, 2 H, aromatic), 7.44 (d, 2 H, aromatic),7.15 (t, 1 H, aromatic), 6.92 (d, 1 H, aromatic), 6.77 (d, 1 H,aromatic), 6.65 (s, 1 H, aromatic), 5.91 (d, 1 H, aromatic), 2.27 (s, 3H, CH₃), 1.66 (s, 3 H, CH₃).

[0957] MS m/z 349 [M⁺+1].

Example 81 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one

[0958]

[0959] To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 3,5-dimethyl-1 H-pyrrole-2-carbaldehyde (32 mg,0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). Thereaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (60 mg, 68%).

[0960]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.24 (br s, 1 H, pyrrole NH), 10.96(br s, 1H, CONH), 7.56 (m, 2 H, aromatic), 7.50 (s, 1 H, aromatic), 7.39(m, 1 H, aromatic), 7.16 (t, 1 H, aromatic), 6.93 (d, 1 H, aromatic),6.78 (d, 1 H, aromatic), 6.75 (s, 1 H, aromatic), 5.92 (d, 1 H,aromatic), 2.28 (s, 3 H, CH₃), 1.66 (s, 3 H, CH₃).

[0961] MS m/z 349 [M⁺+1].

Example 82 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one

[0962]

[0963] To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 3,5-dimethyl-1 H-pyrrole-2-carbaldehyde (32 mg, 0.26mmol) in ethanol (2 mL) was added piperidine (3 drops). The reactionmixture was stirred at room temperature for three days. A yellow solidproduct was precipitated out, filtered, washed by ethanol for threetimes, and dried under high vacuum to provide pure product3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-bromo-phenyl)-1,3-dihydro-one indol-2-oneas a yellow solid (50 mg, 51%).

[0964]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.21 (br s, 1 H, pyrrole NH), 10.94(br s, 1 H, CONH), 7.73 (d, 2 H, aromatic), 7.38 (d, 2 H, aromatic),7.15 (t, 1 H, aromatic), 6.92 (d, 1 H,aromatic), 6.77 (d, 1 H,aromatic), 6.63 (s, 1 H, aromatic), 5.91 (d, 1 H, aromatic), 2.27 (s, 3H, CH₃), 1.66 (s, 3 H, CH₃).

[0965] MS m/z 393 [M⁺+1].

Example 83 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one

[0966]

[0967] To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72mg, 0.25 mmol) and 3,5-dimethyl-1 H-pyrrole-2-carbaldehyde (32 mg, 0.26mmol) in ethanol (2 mL) was added piperidine (3 drops). The reactionmixture was stirred at room temperature for three days. A yellow solidproduct was precipitated out, filtered, washed by ethanol for threetimes, and dried under high vacuum to provide pure product3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one as ayellow solid (71 mg, 71%).

[0968]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.24 (br s, 1 H, pyrrole NH), 10.95(br s, 1 H, CONH), 7.70 (m, 1 H, aromatic), 7.64 (s, 1 H, aromatic),7.51 (t, 1 H, aromatic), 7.44 (d, 1 H, aromatic), 7.16 (t, 1 H,aromatic), 6.93 (d, 1 H, aromatic), 6.78 (d, 1 H, aromatic), 6.74 (s, 1H, aromatic), 5.92 (d, 1 H, aromatic), 2.28 (s, 3 H, CH₃), 1.67 (s, 3 H,CH₃).

[0969] MS m/z 393 [M⁺+1].

Example 84 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one

[0970]

[0971] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 3,5-dimethyl-1 H-pyrrole-2-carbaldehyde (32 mg,0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). Thereaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one asa yellow solid (57 mg, 66%).

[0972]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.22 (br s, 1 H, pyrrole NH), 10.89(br s, 1 H, CONH), 7.32 (d, 2 H, aromatic), 7.11 (m, 3 H, aromatic),6.87 (d, 1 H, aromatic), 6.75 (m, 2 H, aromatic), 5.89 (d, 1 H,aromatic), 3.82 (s, 3 H, CH₃), 2.27 (s, 3 H, CH₃), 1.64 (s, 3 H, CH₃).

[0973] MS m/z 345 [M⁺+1].

Example 85 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one

[0974]

[0975] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 3,5-dimethyl-1 H-pyrrole-2-carbaldehyde (32 mg,0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). Thereaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one asa yellow solid (60 mg, 69%).

[0976]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.23 (br s, 1 H, pyrrole NH), 10.91(br s, 1 H, CONE), 7.45 (t, 1 H, aromatic), 7.14 (t, 1 H, aromatic),7.04 (m, 1 H, aromatic), 6.97 (m, 2 H, aromatic), 6.90 (d, 1 H,aromatic), 6.85 (s, 1 H, aromatic), 6.78 (d, 1 H, aromatic), 5.90 (d, 1H, aromatic), 3.77 (s, 3 H, OCH₃), 2.27 (s, 3 H, CH₃), 1.64 (s, 3 H,CH₃).

[0977] MS m/z 345 [M⁺+1].

Example 865-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0978]

[0979] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (98.6 mg, 86%).

[0980]¹ H-NMR(400 MHz, DMSO-d₆) δ 13.45 (br s, 1 H,pyrrole NH), 11.11(br s, 1 H, CONH), 7.68 (m, 2 H, CONH and aromatic), 7.42 (m, 4 H,aromatic), 7.21 (t, 1 H, aromatic), 6.93 (d, 1 H, aromatic), 6.79 (m, 3H, aromatic), 3.21 (m, 2 H, CH₂), 2.49 (m, 6 H, 3×CH₂), 1.84 (s, 3 H,CH₃), 0.95 (t, 6 H, 2×CH₃).

[0981] MS m/z 461 [M⁺+1].

Example 875-[4-(3-Fluorophenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0982]

[0983] To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (71.0 mg, 62%).

[0984]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.12(br s, 1 H, CONH), 7.72 (t, 1 H, CONH), 7.67 (d, 1 H, aromatic), 7.60(dd, 1 H, aromatic), 7.33 (m, 3 H, aromatic), 7.22 (t, 1 H, aromatic),6.94 (d, 1 H, aromatic), 6.87 (s, 1 H, aromatic), 6.82 (d, 2 H,aromatic), 3.20 (m, 2 H, CH₂), 2.46 (m, 6 H, 3×CH₂), 1.84 (s, 3 H, CH₃),0.95 (t, 6 H, 2×CH₃).

[0985] MS m/z 461 [M⁺+1].

Example 885-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0986]

[0987] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (76.6 mg, 64%).

[0988]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.45 (br s, 1 H, pyrrole NH), 11.11(br s, 1 H, CONH), 7.70 (t, 1 H, CONH), 7.67 (d, 1 H, aromatic), 7.62(d, 2 H, aromatic), 7.46 (d, 2 H, aromatic), 7.22 (t, 1 H, aromatic),6.93 (d, 1 H, aromatic), 6.81 (d, 1 H, aromatic), 6.74 (s, 1 H,aromatic), 3.20 (m, 2 H, CH₂), 2.49 (m, 6 H, 3×CH₂), 1.84 (s, 3 H, CH₃),0.95 (t, 6 H, 2×CH₃).

[0989] MS m/z 477 [M⁺+1].

Example 895-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0990]

[0991] To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (86.2 mg, 72%).

[0992]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1 H, pyrrole NH), 11.13(br s, 1 H, CONH), 7.73 (t, 1 H, CONH), 7.68 (d, 1 H, aromatic), 7.58(m, 2 H, aromatic), 7.53 (s, 1 H, aromatic), 7.41 (m, 1 H, aromatic),7.22 (t, 1 H, aromatic), 6.94 (d, 1 H, aromatic), 6.87 (s, 1 H,aromatic), 6.82 (d, 1 H, aromatic), 3.20 (m, 2 H, CH₂), 2.47 (m, 6 H,3×CH₂), 1.85 (s, 3 H, CH₃), 0.95 (t, 6 H, 2×CH₃).

[0993] MS m/z 477 [M⁺+1].

Example 905-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0994]

[0995] To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (93.5 mg, 72%).

[0996]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1 H, pyrrole NH), 11.13(br s, 1 H, CONH), 7.72 (m, 2 H, CONH and aromatic), 7.67 (m, 2 H,aromatic), 7.53 (t, 1 H, aromatic), 7.45 (d, 1 H, aromatic), 7.22 (t, 1H, aromatic), 6.94 (d, 1 H, aromatic), 6.86 (s, 1 H, aromatic), 6.82 (d,1 H, aromatic), 3.20 (m, 2 H, CH₂), 2.47 (m, 6 H, 3×CH₂), 1.86 (s, 3 H,CH₃), 0.95 (t, 6 H, 2×CH₃).

[0997] MS m/z 521 [M⁺+1].

Example 915-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[0998]

[0999] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (90.4 mg,76.5%).

[1000]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.46 (br s, 1 H, pyrrole NH), 11.06(br s, 1 H, CONH), 7.69 (t, 1 H, CONH), 7.65 (d, 1 H, aromatic), 7.33(d, 2 H, aromatic), 7.19 (t, 1 H, aromatic), 7.11 (d, 2 H, aromatic),6.89 (d, 1 H, aromatic), 6.86 (s, 1 H, aromatic), 6.79 (d, 1 H,aromatic), 3.83 (S, 3 H, OCH₃), 3.20 (m, 2 H, CH₂), 2.47 (m, 6 H,3×CH₂), 1.83 (s, 3 H, CH₃), 0.95 (t, 6 H, 2×CH₃).

[1001] MS m/z 473 [M⁺+1].

Example 925-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-l-9-4-methyl-1 H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[1002]

[1003] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The solvent was evaporated and the solid waswashed by ether for three times to provide pure product5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (67.5 mg, 57%).

[1004]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.06(br s, H, CONH), 7.70 (t, 1 H, CONH), 7.66 (d, 1 H, aromatic), 7.47 (t,1 H, aromatic), 7.20 (t, 1 H, aromatic), 7.07 (dd, 1 H, aromatic), 6.98(m, 2 H, aromatic), 6.86 (s, 1 H, aromatic), 6.91 (d, 1 H, aromatic),6.81 (d, 1 H, aromatic), 3.78 (s, 3 H, OCH₃), 3.20 (m, 2 H, CH₂), 2.48(m, 6 H, 3×CH₂), 1.82 (s, 3 H, CH₃), 0.95 (t, 6 H, 2×CH₃). [0787j MSm/z473 [M⁺+1].

Example 93 3-[3,5-Dimethyl4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1005]

[1006] To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The solvent was evaporated and the solid waswashed by ether for three times to provide pure product3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one(59.5 mg, 52%)

[1007]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1 H, pyrrole NH), 11.07(br s, 1 H, CONH), 7.56 (m, 1 H, aromatic), 7.43 (m, 3 H, aromatic),7.21 (t, 1 H, aromatic), 6.97 (d, 1 H, aromatic), 6.83 (d, 1 H,aromatic), 6.62 (s, 1 H, aromatic), 3.37 (m, 4 H, 2×CH₂), 2.24 (m, 7 H,2×CH₂+CH₃), 2.16 (s, 3 H, CH₃), 1.55 (s, 3 H, CH₃).

[1008] MS m/z 457 [M⁻−1].

Example 945-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[1009]

[1010] To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-anide (69.0 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (98 mg, 83%).

[1011]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1 H, pyrrole NH), 11.08(br s, 1 H, CONH), 7.57 (m, 1 H, aromatic), 7.42 (m, 4 H, aromatic andCONH), 7.22 (t, 1 H, aromatic), 6.97 (d, 1 H, aromatic), 6.83 (d, 1 H,aromatic), 6.65 (s, 1 H, aromatic), 3.22 (dd, 2 H, CH₂), 2.49 (m, 6 H,3×CH₂), 2.39 (s, 3 H, CH₃), 1.69 (s, 3 H, CH₃), 0.95 (t, 6 H, 2×CH₃).

[1012] MS m/z473 [M⁻−1].

Example 955-[4-(2-Fluorophenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[1013]

[1014] To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product5-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (62.5 mg, 53%).

[1015]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1 H, pyrrole NH), 11.08(br s, 1 H, CONH), 7.57 (m, 1 H, aromatic), 7.45 (m, 4 H, aromatic andCONH), 7.22 (t, 1 H, aromatic), 6.97 (d, 1 H, aromatic), 6.83 (d, 1 H,aromatic), 6.65 (s, 1 H, aromatic), 3.28 (dd, 2 H, CH₂), 2.52 (m, 6 H,3×CH₂), 2.37 (s, 3 H, CH₃),1.68 (m, 7 H, CH₃ and 2×CH₂).

[1016] MS m/z 471 [M⁻−1].

Example 965-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-1i,2,3]triazol-1-yl-ethyl)-amide

[1017]

[1018] To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol(2 mL) was added piperidine (3 drops). The reaction mixture was stirredat room temperature for three days. A yellow solid product wasprecipitated out, filtered, washed by ethanol for three times, and driedunder high vacuum to provide pure product5-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (52.8 mg, 45%).

[1019]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1 H, pyrrole NH), 11.07(br s, 1 H, CONH), 8.10 (s, 1 H, aromatic), 7.71 (s, 1 H, aromatic),7.59 (m, 2 H, aromatic) 7.44 (m, 3 H, aromatic and CONH), 7.21 (t, 1 H,CONH), 6.96 (d, 1 H, aromatic), 6.83 (d, 1 H, aromatic), 6.63 (d, 1 H,aromatic), 4.53 (t, 2 H, CH₂), 3.63 (q, 2 H, CH₂), 2.29 (s, 3 H, CH₃),1.59 (s, 3 H, CH₃).

[1020] MS m/z 469 [M⁻−1].

Example 972-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide

[1021]

[1022] To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellowsolid (57.5 mg, 50%).

[1023]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.90 (br s, 1 H, pyrrole NH), 11.16(br s, 1 H, CONH), 7.90 (s, 1 H, aromatic), 7.50 (t, 1 H, CONH), 7.40(m, 2 H, aromatic), 7.29 (d, 1 H, aromatic), 7.25 (m, 2 H, aromatic),6.96 (d, 1 H, aromatic), 6.78 (d, 1 H, aromatic), 6.38 (s, 1 H,aromatic), 3.20 (dd, 2 H, CH₂), 2.50 (m, 6 H, 3×CH₂), 2.32 (s, 3 H,CH₃), 1.24 (m, 6 H, 2×CH₃).

[1024] MS m/z 461 [M⁺+1].

Example 982-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[1025]

[1026] To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (58.4 mg, 51%).

[1027]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.85 (br s, 1 H, pyrrole NH), 11.36(br s, 1H, CONH), 7.86 (d, 1 H, aromatic), 7.75 (t, 1 H, CONH), 7.42 (m,2 H, aromatic), 7.30 (m, 2 H, aromatic), 7.23 (t, 1 H, aromatic), 6.95(d, 1 H, aromatic), 6.78 (d, 1 H, aromatic), 6.37 (d, 1 H, aromatic),3.14 (dd, 2 H, CH₂), 2.48 (m, 6 H, 3×CH₂), 2.31 (s, 3 H, CH₃), 1.70 (m,4 H, 2×CH₂).

[1028] MS m/z 457 [M⁻−1].

Example 992-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[1029]

[1030] To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1 H-pynole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (74.1 mg, 65%).

[1031]¹ H-NMR(400 MHz, DMSO-d₆) δ 13.86 (br s, 1 H,pyrrole NH), 11.15(br s, 1 H, CONH), 8.01 (t, 1 H, CONH), 7.84 (d, 1 H, aromatic), 7.74(d, 1 H, aromatic), 7.47 (m, 1 H, aromatic), 7.40 (m, 1 H, aromatic),7.32 (t, 1 H, aromatic), 7.35 (m, 2 H, aromatic), 7.23 (t, 1 H,aromatic), 6.97 (d, 1 H, aromatic), 6.80 (d, 1 H, aromatic), 6.32 (d, 1H, aromatic), 4.50 (t, 2 H, CH₂), 3.50 (m, 2 H, CH₂), 2.32 (s, 3 H,CH₃).

[1032] MS m/z 455 [M⁻−1].

Example 100 3-[3-((cis)-3,5-Dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1033]

[1034] To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and3-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (62.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product3-{3-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene} -4-(2-fluoro-phenyl)- I,3-dihydro-indol-2-one asa yellow solid (103.5 mg, 90%).

[1035]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.66 (br s, 1 H, pyrrole NH), 11.13(br s, 1 H, CONH), 7.46 (m, 1 H, aromatic), 7.24 (m, 4 H, aromatic),6.96 (d, 1 H, aromatic), 6.82 (s, 1 H aromatic), 6.78 (d, 2 H,aromatic), 6.04 (s, 1 H, aromatic), 4.12 (m, 1 H, CH), 3.41 (m, 1 H,CH), 2.44 (m, 6 H, CH+CH₂+CH₃), 2.05 (m, 1 H, CH), 1.04 (m, 3 H, CH₃),0.81 (m, 3 H, CH₃).

[1036] MS m/z 457 [M⁻−1].

Example 1015-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide

[1037]

[1038] To a solution of 4-(4-fluoro-phenyl)-I,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide as a yellowsolid (74.4 mg, 61%).

[1039]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1 H, pyrrole NH), 11.04(br s, 1 H, CONH), 7.55 (t, 1 H, aromatic), 7.45 (m, 2 H, aromatic),7.37 (t, 1 H aromatic), 7. 18 (t, 1 H, CONH), 6.92 (d, 1 H, aromatic),6.78 (d, 1 H, aromatic), 6.71 (s, 1 H, aromatic), 3.18 (m, 2 H, CH₂),2.44 (m, 6 H, 3×CH₂), 2.37 (s, 3 H, CH₃), 1.73 (s, 3 H, CH₃), 1.57 (m, 2H, CH₂), 0.96 (t, 6 H, 2×CH₃).

[1040] MS m/z 487 [M⁻−1].

Example 1022-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide

[1041]

[1042] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(3-pyrrolidin-1-yl-propyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product2-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide as a yellowsolid (93.2 mg, 79%).

[1043]¹ H-NMR (400 MHz, DMSO-d6) δ 13.88 (br s, 1 H, pyrrole NH), 11.04(br s, 1 H, CONH), 7.93 (s, 1 H, aromatic), 7.86 (t, 1 H, CONH), 7.36(m, 2 H, aromatic), 7.20 (m, 3 H, aromatic), 6.90 (d, 1 H, aromatic),6.74 (d, 1 H, aromatic), 6.34 (s, 1 H, aromatic), 3.10 (m, 2 H, CH₂),2.40 (m, 6 H, 3×CH₂), 2.29 (s, 3 H, CH₃), 1.68 (m, 4 H, 2×CH₂), 1.59 (m,2 H, CH₂).

[1044] MS m/z 471 [M⁻−1].

Example 1035-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide

[1045]

[1046] To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylicacid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide as a yellowsolid (57.3 mg, 47%).

[1047]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1 H, pyrrole NH), 11.07(br s, 1 H, CONH), 7.59 (m, 2 H, aromatic), 7.32 (m, 3 H, aromatic),7.20 (t, 1 H, CONH), 6.94 (d, 1 H, aromatic), 6.73 (m, 2 H, aromatic),3.18 (m, 2 H, CH₂), 2.45 (m, 6 H, 3×CH₂), 2.37 (s, 3 H, CH₃), 1.72 (s, 3H, CH₃), 1.57 (m, 2 H, CH₂), 0.93 (t, 6 H, 2×CH₃).

[1048] MS m/z 487 [M⁻−1].

Example 104 3-[3,5-Dimethyl4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one

[1049]

[1050] To a solution of4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25mmol) and 3,5-dimethyl4-4 (4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. The solvent was evaporated and the solid waswashed by ether for three times to provide pure product3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one(96.5 mg, 76%).

[1051]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.44 (br s, 1 H, pyrrole NH), 11.10(br s, 1 H, CONH), 7.76 (m, 4 H, aromatic), 7.22 (t, 1 H, aromatic),6.95 (d, 1 H, aromatic), 6.83 (d, 1 H, aromatic), 6.58 (s, 1 H,aromatic), 3.38 (m, 4 H, 2×CH₂), 2.29 (m, 7 H, 2×CH₂+CH₃), 2.17 (s, 3 H,CH₃), 1.54 (s, 3 H, CH₃). [08231 MS m/z 507 [M⁻−1].

Example 1052,4-Dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydroindol-3-ylidenemethyl]-1 H-pyrrole-3-carboxylic acid(2-diethylaminoethyl)-amide

[1052]

[1053] To a solution of 4-(3-trifluoromethyl-phenyl)-I1,3-dihydro-indo1-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26mmol) in ethanol (2 mL) was added pipenidine (3 drops). The reactionmixture was stirred at room temperature for three days. A yellow solidproduct was precipitated out, filtered, washed by ethanol for threetimes, and dried under high vacuum to provide2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamnino-ethyl)-amide as a yellowsolid (68 mg, 52%).

[1054]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1 H, pyrrole NH), 11.10(br s, 1 H, CONH), 7.80 (m, 1 H, aromatic), 7.7 (m, 3 H, aromatic), 7.31(s, 1 H, CONH), 7.21 (m, 1 H, aromatic), 6.97 (d, 1 H, aromatic), 6.83(d, 1 H, aromatic), 6.61 (s, 1 H, aromatic), 3.22 (m, 2 H, CH₂), 2.40(m, 6 H, 3×CH₂), 2.34 (s, 3 H, CH₃), 1.68 (s, 3 H, CH₃), 0.94 (m, 6 H,2×CH₃).

[1055] MS m/z 523 [M⁻−1].

Example 106 2,4-Dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[1056]

[1057] To a solution of4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-I,2-dihydro-indol-3-ylidenemethyl]-1 H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (69.2 mg, 53%).

[1058]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1 H, pyrrole NH), 11.10(br s, 1 H, CONH), 7.82 (m, 4 H, aromatic), 7.44 (t, 1 H, CONH), 7.22(t, 1 H, aromatic), 6.97 (dd, 1 H, aromatic), 6.43 (dd, 1 H, aromatic),6.61 (s, 2 H, aromatic), 3.28 (m, 2 H, CH₂), 2.51 (m, 2 H, CH₂), 2.44(m, 4 H, 2×CH₂), 2.37 (s, 3 H, CH₃), 1.66 (s, 3 H, CH₃), 1.62 (m, 4 H2×CH₂).

[1059] MS m/z 523 [M⁺+1].

Example 1072,4-Dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[1060]

[1061] To a solution of4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (53 mg, 41%).

[1062]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.48 (br s, 1 H, pyrrole NH), 11.06(br s, =1 H, CONH), 8.10 (s, 1 H, aromatic), 7.81 (m, 4 H, aromatic),7.71 (d, 1 H, aromatic), 7.63 (s, 1 H, CONH+aromatic), 7.22 (t, 1 H,aromatic), 6.66 (dd, 1 H, aromatic), 6.83 (dd, 1 H, aromatic), 6.59 (s,1 H, aromatic), 4.52 (t, 2 H, CH₂), 3.64 (m, 2 H, CH₂), 2.28 (s, 3 H,CH₃), 1.54 (s, 3 H, CH₃).

[1063] MS m/z 519 [M⁻−1].

Example 1085-Methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole3-carboxylic acid (2-diethylamino-ethyl)-amide

[1064]

[1065] To a solution of4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25mmol) and 2-formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-I,2-dihydro-indol-3-ylidenemethyl]-1 H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide as a yellow solid (28 mg, 22%).

[1066]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.81 (br s, 1 H, pyrrole NH), 11.15(br s, 1 H, CONH), 8.01 (s, 1 H, aromatic), 7.66 (m, 5 H,CONH+aromatic), 7.23 (t, 1 H, aromatic), 6.95 (d, 1 H, aromatic), 6.80(dd, 1 H, aromatic), 6.36 (d, 1 H, aromatic), 3.33 (m, 2 H, CH₂), 2.50(m, 6 H, 3×CH₂), 2.31 (s, 3 H, CH₃), 0.98 (t, 6 H, 2×CH₃).

[1067] MS m/z 509 [M⁻−1].

Example 1095-Methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[1068]

[1069] To a solution of4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25mmol) and 2-formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellowsolid (95 mg, 75%).

[1070]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.79 (br s, 1 H, pyrrole NH), 11.15(br s, 1 H, CONH), 7.99 (s, 1 H, aromatic), 7.70 (m, 5 H,CONH+aromatic), 7.23 (t, 1 H, aromatic), 6.95 (dd, 1 H, aromatic), 6.82(dd, 1 H, aromatic), 6.39 (m, 1 H, aromatic), 3.13 (m, 2 H, CH₂), 2.47(m, 6 H, 3×CH₂), 2.31 (s, 3 H, CH₃), 1.69 (m, 4 H 2×CH₂).

[1071] MS m/z 509 [M⁺+1].

Example 1105-Methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[1072]

[1073] To a solution of4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25mmol) and 2-formyl-5-methyl-1 H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as ayellow solid (93.6 mg, 74%).

[1074]¹ H-NMR(400 MHz, DMSO-d₆) δ 13.80 (br s, 1 H, pyrrole NH), 11.17(br s, 1 H, CONH), 8.01 (m, 1 H, aromatic), 7.96 (dd, 2 H, aromatic),7.77 (m, 1 H, aromatic), 7.73 (d, 1 H, aromatic),7.68 (m, 3 H,aromatic), 7.72 (t, 1 H, aromatic), 6.96 (dd, 1 H, aromatic), 6.83 (dd,1 H, aromatic), 6.34 (d, 1 H aromatic), 4.45 (t, 2 H, CH₂), 3.44 (m, 2H, CH₂), 2.30 (s, 3 H, CH₃).

[1075] MS m/z 505 [M⁻−1].

Example 111 3-[3-((cis)-3,5-Dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(2-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one

[1076]

[1077] To a solution of4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25mmol) and 3-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (62.3 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product3-[3-((cis)-3,5-dimethyl-peperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(2-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-oneas a yellow solid (92.7 mg, 73%).

[1078]¹ H-NMR (400 MHz, DMSO-d₆) δ 13.61 (br s, 1 H, pyrrole NH), 11.15(br s, H), 7.70 (m, 4 H, aromatic), 7.22 (t, 1 H, aromatic), 6,95 (dd, 1H, aromatic), 1 H, aromatic), 6.69 (d, 1 H, aromatic), 6.00 (d, 1 H,aromatic), 4.01 (m, 1 H, 47 (m, 1 H, CH), 2.32 (m, 4 H, 2×CH₂), 2.32 (m,3 H, CH₃), 0.96 (m, 6 H,

[1079] MS m/z 507 [M⁻−1].

Example 1122,4-Dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-diethylamino-propyl)-amide

[1080]

[1081] To a solution of4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-diethylamino-propyl)-amide as a yellow solid (72.6 mg, 54%).

[1082]¹H-NMR (400 MHz, DMSO-d6) δ 13.48 (br s, 1H, pyrrole NH), 11.00(br s, 1H, CONH), 7.88 (m, 1H, aromatic), 7.78 (m, 3H, aromatic), 7.60(m, 1H, aromatic), 7.22 (t, 1H, aromatic), 6.97 (d, 1H, aromatic), 6.83(d, 1H, aromatic), 6.61 (s, 1H, aromatic), 3.32 (m, 2H, CH₂), 3.20 (m,2H, CH₂), 2.49 (m, 6H, 3×CH₂), 2.37 (s, 3H, CH₃), 1.61 (s, 3H, CH₃),0.96 (s, 6H, 2×CH₃).

[1083] MS m/z 537 [M⁻−1].

Example 1135-Methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1084]

[1085] To a solution of4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(3-pyrrolidin-1-yl-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (52.2 mg, 40%).

[1086]¹H-NMR (400 MHz, DMSO-d₆) δ 13.85 (br s, 1H, pyrrole NH), 11.05(br s, 1H, CONH), 7.95 (s, 1H, aromatic), 7.85 (t, 1H, CONH), 7.67 (m,4H, aromatic), 7.22 (t, 1H, aromatic), 6.96 (d, 1H, aromatic), 6.80 (dd,1H, aromatic), 6.35 (d, 1H, aromatic), 3.42 (s, 2H, CH2), 3.10 (q, 2H,CH₂), 2.49 (m, 6H, 3×CH₂), 2.30 (s, 3H, CH₃), 1.69 (m, 4H 2×CH₂).

[1087] MS m/z 521 [M⁻−1].

Example 1143-[3-Methyl4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one

[1088]

[1089] To a solution of4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25mmol) and3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde(61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-oneas a yellow solid (46.9 mg, 38%).

[1090]¹H-NMR (400 MHz, DMSO-d₆) δ 13.45 (br s, 1H, pyrrole NH), 11.16(br s, 1H, CONH), 7.98 (m, 1H, aromatic), 7.80 (m, 3H, aromatic), 7.39(d, 1H, aromatic), 7.25 (t, 1H, aromatic), 6.96 (dd, 1H, aromatic), 6.85(d, 1H, aromatic), 6.66 (s, 1H, aromatic), 3.38 (m, 4H, 2×CH₂), 2.25 (m,4H, 2×CH₂), 2.17 (s, 3H, CH₃), 1.56 (s, 3H, CH₃).

[1091] MS m/z 493 [M⁻−1].

Example 1153-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-Methyl-1H-pyrrol-2-ylmethylene]4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one

[1092]

[1093] To a solution of4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25mmol) and4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde(64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-{4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(3-trifluoromethyl-phenyl)-1,3dihydro-indol-2-oneas a yellow solid (34.3 mg, 27%).

[1094]¹H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1H, pyrrole NH), 11.16(br s, 1H, CONH), 7.88 (m, 1H, aromatic), 7.81 (m, 3H, aromatic), 7.6(dd, 1H, aromatic), 7.25 (t, 1H, aromatic), 6.96 (d, 1H, aromatic), 6.85(d, 1H, aromatic), 6.66 (s, 1H, aromatic), 3.32 (m, 1H, CH), 2.46 (m,1H, CH), 2.50 (m, 4H, 2×CH₂), 1.54 (s, 3H, CH₃), 0.92 (m, 6H, 2×CH₃).

[1095] MS m/z 507 [M⁻−1].

Example 1164-(3-Chloro-4-fluoro)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[1096]

[1097] To a solution of4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25mmol) and3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde(64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Thesolvent was evaporated and the solid was washed by ether for three timesto provide pure product4-(3-chloro-4-fluoro)-3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one(59 mg, 48%).

Example 1175-[4-(3-Chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide

[1098]

[1099] To a solution a solution of4-(3-Chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-2-one (65.4 mg,0.25 mmol) and 5-formyl-2,4- dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 ml) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide5-[4-(3-Chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide (72 mg, 57%).

[1100]¹H-NMR (400 MHz), DMSO-d₆) δ13.47 (br s, 1H, pyrrole NH), 11.07(br s, 1H, CONH), 7.70 (d, 1H aromatic), 7.61 (t, 1H, CONH), 7.46 (m, 1Haromatic), 7.35 (m, 1H, aromatic), 7.20 (t, 1H, aromatic), 6.95 (d, 1H,aromatic), 6.82 (d, 1H, aromatic), 6.73 (d, 1H, aromatic), 3,24 (m, 2H,CH₂), 2.50 (m, 6H, 3×CH₂), 2.38 (s, 3H, CH₃), 1.78 (s, 3H, CH₃), 0.95(t, 6H, 2×CH₃).

[1101] MS m/z 507 [M⁻−1].

Example 1185-[4-(3-Chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[1102]

[1103] To a solution of4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product5-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (53 mg, 45%).

[1104]¹H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1H, pyrrole NH), 11.07(br s, 1H, CONH), 8.10 (s, 1H, aromatic), 7.70 (m, 2H, aromatic), 7.63(t, 2H, CONH+aromatic), 7.46 (m, 1H, aromatic), 7.19 (t, 1H, aromatic),6.93 (d, 1H, aromatic), 6.80 (d, 1H, aromatic), 6.71 (s, 1H, aromatic),4.53 (m, 2H, CH₂), 3.64 (m, 2H, CH₂), 2.30 (s, 3H, CH₃), 1.69 (s, 3H,CH₃).

[1105] MS m/z 503 [M⁻−1].

Example 1192-]4-(3-Chloro-4-fluoro-phenyl)-2-oxo1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1106]

[1107] To a solution of4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4mg, 0.25 mmol)and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (89 mg, 72%).

[1108]¹H-NMR (400 MHz, DMSO-d₆) δ 13.79 (br s, 1H, pyrrole NH), 11.13(br s, 1H, CONH), 8.03 (s, 1H, aromatic), 7.80 (t, 1H, CONH), 7.50 (d,1H, aromatic), 7.42 (t, 1H, aromatic), 7.32 (m, 1H, aromatic), 7.21 (t,1H, aromatic), 6.93 (d, 1H, aromatic), 6.78 (d, 1H, aromatic), 6.43 (s,1H, aromatic), 3.21 (m, 2H, CH₂), 2.50 (m, 6H, 3×CH₂), 2.31 (s, 3H,CH₃), 1.67 (m, 4H 2×CH₂).

[1109] MS m/z 491 [M⁻−1].

Example 1202-[4-(3-Chloro-4--fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[1110]

[1111] To a solution of4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product2-[4-(3-chloro-4--fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (85 mg, 69%).

[1112]¹H-NMR (400 MHz, DMSO-d₆) δ 13.81 (br s, 1H, pyrrole NH), 11.15(br s, 1H, CONH), 8.07 (m, 1H, aromatic), 7.98 (d, 2H, aromatic), 7.74(s, 1H, aromatic), 7.52 (d, 1H, aromatic), 7.47 (t, 1H, aromatic), 7.32(m, 1H, aromatic), 7.22 (t, 1H, aromatic), 6.94 (d, 1H, aromatic), 6.78(d, 1H, aromatic), 6.36 (s, 1H, aromatic), 4.53 (m, 2H, CH₂), 3.53 (m,2H, CH₂), 2.30 (s, 3H, CH₃).

[1113] MS m/z 489 [M⁻−1].

Example 1212-[4-(3-Chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1114]

[1115] To a solution of4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid(3-pyrrolidin-1-yl-propyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (103 mg, 81%).

[1116]¹H-NMR (400 MHz, DMSO-d₆) δ 13.86 (br s, 1H, pyrrole NH), 11.05(br s, 1H, CONH), 8.01 (s, 1H, aromatic), 7.91 (t, 1H, CONH), 7.50 (d,1H, aromatic), 7.41 (t, 1H, aromatic), 7.31 (m, 1H, aromatic), 7.20 (t,1H, aromatic), 6.93 (d, 1H, aromatic), 6.77 (d, 1H, aromatic), 6.40 (s,1H, aromatic), 3.32 (m, 2H, CH₂), 3.14 (m, 2H, CH₂), 2.41 (m, 6H,3×CH₂), 2.31 (s, 3H, CH₃), 1.67 (m, 4H 2×CH₂),

[1117] MS m/z 506 [M⁻−1].

Example 1224-(4-Chloro-phenyl)-3-{3,5-dimethyl4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-ylmethylene}-1,3-dihydro-indol-2-one

[1118]

[1119] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde(72.1 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product4-(4-chloro-phenyl)-3-{3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-ylmethylene}-1,3-dihydro-indol-2-oneas a yellow solid (47.4 mg, 38%).

[1120]¹H-NMR (400 MHz, DMSO-d₆) δ 13.27 (br s, 1H, pyrrole NH), 11.40(br s, 1H, CONH), 7.60 (d, 2H, aromatic), 7.42 (dd, 2H, aromatic), 7.10(t, 1H, aromatic), 6.91 (d, 1H, aromatic), 6.75 (d, 1H, aromatic), 6.66(s, 1H, aromatic), 3.40 (m, 4H, 2×CH₂), 2.52 (m, 4H, 2×CH₂), 2.36 (m,4H, 2×CH₂), 2.24 (s, 3H, CH₃), 2.19 (s, 3H, CH₃), 1.59 (s, 3H, CH₃).

[1121] MS m/z 503 [M⁺+].

Example 1234-(2-Fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[1122]

[1123] To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde(61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product4-(2-fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-oneas a yellow solid (40 mg, 36%).

[1124]¹H-NMR (400 MHz, DMSO-d₆) δ 13.51 (br s, 1H, pyrrole NH), 11.15(br s, 1H, CONH), 7.57 (m, 1H, aromatic), 7.42 (m, 4H, aromatic), 7.25(t, 1H, aromatic), 6.97 (d, 1H, aromatic), 6.85 (d, 1H, aromatic), 6.69(s, 1H, aromatic), 3.40 (m, 4H, 2×CH₂), 2.25 (m, 4H, 2×CH₂), 2.17 (s,3H, CH₃), 1.62 (s, 3H, CH₃).

[1125] MS m/z 445 [M⁺+1].

Example 1244-(4-Fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[1126]

[1127] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde(61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product4-(4-fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-oneas a yellow solid (39 mg, 36%).

[1128]¹H-NMR (400 MHz, DMSO-d₆) δ 13.50 (br s, 1H, pyrrole NH), 11.12(br s, 1H, CONH), 7.48 (m, 2H, aromatic), 7.39 (m, 3H, aromatic), 7.22(t, 1H, aromatic), 6.93 (d, 1H, aromatic), 6.80 (t, 2H, aromatic), 3.45(m, 4H, 2×CH₂), 2.26 (m, 4H, 2×CH₂), 2.17 (s, 3H, CH₃), 1.67 (s, 3H,CH₃).

[1129] MS m/z 445 [M⁺+].

Example 1254-(4-Chloro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[1130]

[1131] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde(61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product4-(4-chloro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-oneas a yellow solid (47 mg, 35%).

[1132]¹H-NMR (400 MHz, DMSO-d₆) δ 13.46 (br s, 1H, pyrrole NH), 11.12(br s, 1H, CONH), 7.60 (dd, 2H, aromatic), 7.42 (d, 2H, aromatic), 7.30(d, 1H, aromatic), 7.20 (t, 1H, aromatic), 6.90 (d, 1H, aromatic), 6.80(d, 1H, aromatic), 6.72 (s, 1H, aromatic), 3.44 (m, 4H, 2×CH₂), 2.26 (m,4H, 2×CH₂), 2.17 (s, 3H, CH₃), 1.67 (s, 3H, CH₃).

[1133] MS m/z 461 [M⁺+].

Example 1264-(4-Bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[1134]

[1135] To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0mg, 0.25 mmol) and3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde(61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product4-(4-bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-oneas a yellow solid (42.8 mg, 34%).

[1136]¹H-NMR (400 MHz, DMSO-d₆) δ13.46 (br s, 1H, pyrrole NH), 11.12 (brs, 1H, CONH), 7.75 (d, 2H, aromatic), 7.40 (d, 3H, aromatic), 7.23 (t,1H, aromatic), 6.93 (d, 1H, aromatic), 6.81 (d, 1H, aromatic), 6.71 (s,1H, aromatic), 3.46 (m, 4H, 2×CH₂), 2.26 (m, 4H, 2×CH₂), 2.17 (s, 3H,CH₃), 1.67 (s, 3H, CH₃).

[1137] MS m/z 507 [M⁺+].

Example 1274-(3-Bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[1138]

[1139] To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0mg, 0.25 mmol) and3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde(61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product4-(3-bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-oneas a yellow solid (61.4 mg, 49%).

[1140]¹H-NMR (400 MHz, DMSO-d₆) δ 13.50 (br s, 1H, pyrrole NH), 11.14(br s, 1H, CONH), 7.72 (dd, 1H, aromatic), 7.67 (d, 1H, aromatic), 7.53(t, 1H, aromatic), 7.45 (d, 1H, aromatic), 7.40 (d, 1H, aromatic), 7.23(d, 1H, aromatic), 6.94 (s, 1H, aromatic), 6.82 (d, 2H, aromatic), 3.46(m, 4H, 2×CH₂), 2.26 (m, 4H, 2×CH₂), 2.17 (s, 3H, CH₃), 1.67 (s, 3H,CH₃).

[1141] MS m/z 504 [M⁺+].

Example 1284-(4-Methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[1142]

[1143] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde(61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product4-(4-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-oneas a yellow solid (94 mg, 82%).

[1144]¹H-NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1H, pyrrole NH), 11.08(br s, 1H, CONH), 7.74 (d, 1H, aromatic), 7.35 (d, 1H, aromatic), 7.33(s, 1H, aromatic), 7.20 (t, 1H, aromatic), 7.11 (m, 2H, aromatic), 6.89(d, 1H, aromatic), 6.84 (s, 1H, aromatic), 6.79 (d, 1H, aromatic), 3.82(s, 3H, OCH₃), 3.45 (m, 4H, 2×CH₂), 2.25 (m, 4H, 2×CH₂), 2.17 (s, 3H,CH₃), 1.66 (s, 3H, CH₃).

[1145] MS m/z 457 [M⁺+].

Example 1294-(3-Methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[1146]

[1147] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde(61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product4-(3-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-oneas a yellow solid (46.4 mg, 41%).

[1148]¹H-NMR (400 MHz, DMSO-d₆) δ 13.50 (br s, 1H, pyrrole NH), 11.10(br s, 1H, CONH), 7.47 (t, 1H, aromatic), 7.38 (d, 1H, aromatic), 7.20(t, 1H, aromatic), 7.06 (dd, 1H, aromatic), 6.99 (dd, 2H, aromatic),6.91 (d, 2H, aromatic), 6.81 (d, 1H, aromatic), 3.78 (s, 3H, OCH₃), 3.45(m, 4H, 2×CH₂), 2.26 (m, 4H, 2×CH₂), 2.17 (s, 3H, CH₃), 1.65 (s, 3H,CH₃).

[1149] MS m/z 457 [M⁺+1].

Example 1303-[3-Methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one

[1150]

[1151] To a solution of 4-phenyl-1,3-dihydro-indol-2-one (52.3 mg, 0.25mmol) and3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde(61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-oneas a yellow solid (40.6 mg, 38%).

[1152]¹H-NMR (400 MHz, DMSO-d₆) δ 13.50 (br s, 1H, pyrrole NH), 11.11(br s, 1H, CONH), 7.57 (m, 3H, aromatic), 7.44 (dd, 2H, aromatic), 7.36(d, 1H, aromatic), 7.21 (t, 1H, aromatic), 6.92 (dd, 1H, aromatic), 6.80(d, 2H, aromatic), 3.44 (s, 3H, OCH₃), 3.41 (m, 4H, 2×CH₂), 2.25 (m, 4H,2×CH₂), 2.17 (s, 3H, CH₃), 1.59 (s, 3H, CH₃).

[1153] MS m/z 427 [M⁺+].

Example 1313-[4-((cis)-3,5-Dimethyl-piperazine-1l-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1154]

[1155] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde(64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-{4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-oneas a yellow solid (57.8 mg, 50%).

[1156]¹H-NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1H, pyrrole NH), 11.12(br s, 1H, CONH), 7.49 (m, 2H, aromatic), 7.39 (m, 3H, aromatic), 7.21(t, 1H, aromatic), 6.92 (d, 1H, aromatic), 6.80 (t, 2H, aromatic), 4.09(br, 1H, CH), 3.67 (br, 1H, CH), 2.57 (m, 2H, CH₂), 2.26 (m, 2H, 2×CH),1.66 (s, 3H, CH₃), 0.92 (s, 6H, 2×CH₃).

[1157] MS m/z 458 [M⁻−1].

Example 1324-(4-Chloro-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[1158]

[1159] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde(64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product4-(4-chloro-phenyl)-3-{4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-oneas a yellow solid (29 mg, 25%).

[1160]¹H-NMR (400 MHz, DMSO-d₆) δ 13.44 (br s, 1H, pyrrole NH), 11.12(br s, 1H, CONH), 7.61 (m, 2H, aromatic), 7.46 (dd, 2H, aromatic), 7.37(d, 1H, aromatic), 7.22 (t, 1H, aromatic), 6.93 (t, 1H, aromatic), 6.82(d, 1H, aromatic), 6.72 (s, 1H, aromatic), 4.21 (br, 1H, CH), 3.61 (br,1H, CH), 2.57 (m, 2H, CH₂), 2.28 (m, 2H, 2×CH), 1.61 (s, 3H, CH₃), 0.92(m, 6H, 2×CH₃).

[1161] MS m/z 473 [M⁻−1].

Example 1334-(4-Bromo-phenyl)-3-[4-(3,5-dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[1162]

[1163] To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0mg, 0.25 mmol) and4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde(64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product4-(4-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-oneas a yellow solid (79 mg, 61%).

[1164]¹H-NMR (400 MHz, DMSO-d₆) δ 13.43 (br s, 1H, pyrrole NH), 11.12(br s, 1H, CONH), 7.76 (dd, 2H, aromatic), 7.39 (m, 3H, aromatic), 7.22(t, 1H, aromatic), 6.93 (d, 1H, aromatic), 6.81 (d, 1H, aromatic), 6.70(s, 1H, aromatic), 4.20 (br, 1H, CH), 3.60 (br, 1H, CH), 2.58 (m, 2H,CH₂), 2.27 (m, 2H, CH), 1.63 (s, 3H, CH₃), 0.92 (s, 6H, 2×CH₃).

[1165] MS m/z 519 [M⁺+].

Example 1343-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one

[1166]

[1167] To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde(64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-{4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-oneas a yellow solid (74 mg, 63%).

[1168]¹H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1H, pyrrole NH), 11.08(br s, H, CONH), 7.34 (m, 3H, aromatic), 7.19 (t, 1H, aromatic), 7.11(dd, 2H, aromatic), 6.89 (d, 1H, aromatic), 6.84 (s, 1H, aromatic), 6.78(s, 1H, aromatic), 3.82 (s, 3H, OCH₃), 4.45 (br, 1H, CH), 4.0 (br, 1H,CH), 2.58 (m, 2H, CH₂), 2.29 (m, 2H, CH), 1.65 (s, 3H, CH₃), 0.92 (s,6H, 2×CH₃).

[1169] MS m/z 471 [M⁺+1].

Example 1353-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one

[1170]

[1171] To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one(59.8 mg, 0.25 mmol) and4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde(64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-oneas a yellow solid (42 mg, 36%).

[1172]¹H-NMR (400 MHz, DMSO-d₆) δ 13.43 (br s, 1H, pyrrole NH), 11.10(br s, 1H, CONH), 7.46 (q, 1H, aromatic), 7.36 (d, 1H, aromatic), 7.21(t, 1H, aromatic), 7.06 (dd, 1H, aromatic), 6.99 (dd, 2H, aromatic),6.91 (d, 2H, aromatic), 6.81 (d, 1H, aromatic), 3.78 (s, 3H, OCH₃), 4.30(br s, 1H, CH), 4.00 (br, 1H, CH), 2.58 (m, 2H, CH₂), 2.29 (m, 2H, CH),1.64 (s, 3H, CH₃), 0.92 (s, 6H, 2×CH₃).

[1173] MS m/z 469 [M⁻−1].

Example 1363-[4-((cis)-3,5-Dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one

[1174]

[1175] To a solution of 4-phenyl-1,3-dihydro-indol-2-one (52.3 mg, 0.25mmol) and4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde(64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-oneas a yellow solid (21.5 mg, 20%).

[1176]¹H-NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1H, pyrrole NH), 11.10(br s, 1H, CONH), 7.56 (m, 3H, aromatic), 7.44 (d, 2H, aromatic), 7.35(d, 1H, aromatic), 7.22 (d, 1H, aromatic), 6.92 (d, 1H, aromatic), 6.81(m, 2H, aromatic), 4.35 (br, 1H, CH), 3.70 (br, 1H, CH), 2.58 (m, 2H,CH₂), 2.29 (m, 2H, CH), 1.58 (s, 3H, CH₃), 0.92 (s, 6H, 2×CH₃).

[1177] MS m/z 469 [M⁻−1].

Example 1374-(4-Chloro-phenyl)-3-[4-[3-((cis)-3,5-dimethyl-piperazin-1-yl]-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one

[1178]

[1179] To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one(60.9 mg, 0.25 mmol) and3-[(cis)-3,5-dimethyl-piperazin-1-yl]-3-oxo-propyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde(75.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product4-(4-chloro-phenyl)-3-[4-[3-((cis)-3,5-dimethyl-piperazin-1-yl]-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-ylmethylene}-1,3-dihydro-indol-2-oneas a yellow solid (76.7 mg, 60%).

[1180]¹H-NMR (400 MHz, DMSO-d₆) δ 13.25 (br s, 1H, pyrrole NH), 10.90(br s, 1H, CONH), 7.61 (d, 2H, aromatic), 7.42 (d, 2H, aromatic), 7.17(t, 1H, aromatic), 6.91 (d, 1H, aromatic), 6.75 (d, 1H, aromatic), 6.64(s, 1H, aromatic), 4.24 (d, 1H, CH), 3.49 (d, 1H, CH), 3.40 (m, 4H,2×CH₂), 2.35 (m, 4H, 2×CH₂), 2.23 (s, 3H, CH₃), 1.59 (s, 3H, CH₃), 0.92(d, 3H, CH₃), 0.84 (d, 3H, CH₃).

[1181] MS m/z 517 [M⁺+].

Example 1383-[4-[3-((cis)-3,5-Dimethyl-piperazin-1-yl)-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1182]

[1183] To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one(56.8 mg, 0.25 mmol) and3-[(cis)-3,5-dimethyl-piperazin-1-yl]-3-oxo-propyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde(75.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Ayellow solid product was precipitated out, filtered, washed by ethanolfor three times, and dried under high vacuum to provide pure product3-[4-[3-((cis)-3,5-dimethyl-piperazin-1-yl]-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-ylmethylene}-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-oneas a yellow solid (60.7 mg, 49%).

[1184]¹H-NMR (400 MHz, DMSO-d₆) δ 13.27 (br s, 1H, pyrrole NH), 10.89(br s, 1H, CONH), 7.45 (m, 2H, aromatic), 7.36 (t, 2H, aromatic), 7.12(t, 1H, aromatic), 6.90 (d, 1H, aromatic), 6.75 (d, 1H, aromatic), 6.66(s, 1H, aromatic), 4.23 (d, 1H, CH), 3.46 (d, 1H, CH), 3.40 (m, 4H,2×CH₂), 2.37 (m, 4H, 2×CH₂), 2.23 (s, 3H, CH₃), 1.60 (s, 3H, CH₃), 0.92(d, 3H, CH₃), 0.84 (d, 3H, CH₃). 109231 MS m/z 501 [M⁺+].

Example 1393-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one

[1185]

[1186] To a solution of4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25mmol) and3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde(64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops).The reaction mixture was stirred at room temperature for three days. Thesolvent was evaporated and the solid was washed by ether for three timesto provide pure product3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one(79.9 mg, 61%).

[1187]¹H-NMR (400 MHz, DMSO-d₆) δ 13.43 (br s, 1H, pyrrole NH), 11.06(br s, 1H, CONH), 7.57 (m, 4H, aromatic), 7.20 (t, 1H, aromatic), 6.38(d, 1H, aromatic), 6.80 (d, 1H, aromatic), 6.73 (s, 1H, aromatic), 3.32(m, 4H, 2×CH₂), 2.24 (m, 7H, 2×CH₂+CH₃), 2.16 (s, 3H, CH₃), 1.56 (s, 3H,CH₃).

[1188] MS m/z 523 [M⁻−1].

Example 1402,4-Dimethyl-5-[2-oxo4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-diethylaminoethyl)-amide

[1189]

[1190] To a solution of4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) wasadded piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide2,4-dimethyl-5-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide as a yellow solid (75.6 mg, 56%).

[1191]¹H-NMR (400 MHz, DMSO-d₆) δ 13.49 (br s, 1H, pyrrole NH), 11.07(br s, 1H, CONH), 7.57 (m, 3H, aromatic), 7.29 (t, 1H, aromatic), 7.20(t, 1H, aromatic), 6.94 (d, 1H, aromatic), 6.80 (d, 1H, aromatic), 6.74(s, 1H, aromatic), 3.23 (q, 2H, CH₂), 2.49 (m, 6H, 3×CH₂), 2.39 (s, 3H,CH₃), 1.70 (s, 3H, CH₃), 0.95 (t, 6H, 2×CH₃).

[1192] MS m/z 539 [M⁻−1].

Example 1412,4-Dimethyl-5-[2-oxo4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[1193]

[1194] To a solution of4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product2,4-dimethyl-5-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (49.6 mg,37%).

[1195]¹H-NMR (400 MHz, DMSO-d₆) δ 13.47 (br s, 1H, pyrrole NH), 11.07(br s, 1H, CONH), 8.10 (s, 1H, aromatic), 7.67 (m, 1H, aromatic), 7.57(m, 5H, aromatic+CONH), 7.20 (t, 1H, aromatic), 6.93 (d, 1H, aromatic),6.78 (d, 1H, aromatic), 6.73 (s, 1H, aromatic), 4.53 (t, 2H, CH₂), 3.64(q, 2H, CH₂), 2.29 (s, 3H, CH₃), 1.59 (s, 3H, CH₃).

[1196] MS m/z 535 [M⁻−1].

Example 1425-Methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1197]

[1198] To a solution of4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product 5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (93 mg, 71%).

[1199]¹H-NMR (400 MHz, DMSO-d₆) δ 13.87 (br s, 1H, pyrrole NH), 11.13(br s, 1H, CONH), 8.07 (s, 1H, aromatic), 7.74 (t, 1H, CONH), 7.47 (d,2H, aromatic), 7.37 (d, 2H, aromatic), 7.21 (t, 1H, aromatic), 6.93 (d,1H, aromatic), 6.77 (d, 1H, aromatic), 6.41 (d, 1H, aromatic), 3.17 (q,2H, CH₂), 2.49 (m, 6H, 3×CH₂), 2.31 (s, 3H, CH₃), 1.68 (m, 4H, 2×CH₂).

[1200] MS m/z 523 [M⁻−1].

Example 1435-Methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[1201]

[1202] To a solution of4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid(2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2mL) was added piperidine (3 drops). The reaction mixture was stirred atroom temperature for three days. A yellow solid product was precipitatedout, filtered, washed by ethanol for three times, and dried under highvacuum to provide pure product5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (96.6 mg,74%).

[1203]¹H-NMR (400 MHz, DMSO-d₆) δ 13.87 (br s, 1H, pyrrole NH), 11.15(br s, 1H, CONH), 8.00 (m, 3H, aromatic), 7.72 (s, 1H, CONH), 7.49 (m,2H, aromatic), 7.41 (d, 2H, aromatic), 7.21 (t, 1H, aromatic), 6.94 (d,1H, aromatic), 6.78 (d, 1H, aromatic), 6.34 (d, 1H, aromatic), 4.52 (t,2H, CH₂), 3.48 (m, 2H, CH₂), 2.29 (s, 3H, CH₃).

[1204] MS m/z 521 [M⁻−1].

Example 1445-Methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1205]

[1206] To a solution of4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(3-pyrrolidin-1-yl-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL)was added piperidine (3 drops). The reaction mixture was stirred at roomtemperature for three days. A yellow solid product was precipitated out,filtered, washed by ethanol for three times, and dried under high vacuumto provide pure product5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (96.8 mg, 72%).

[1207]¹H-NMR (400 MHz, DMSO-d₆) δ 13.93 (br s, 1H, pyrrole NH), 11.05(br s, 1H, CONH), 8.04 (s, 1H, aromatic), 7.85 (t, 1H, CONH), 7.47 (m,2H, aromatic), 7.35 (d, 1H, aromatic), 7.19 (t, 1H, aromatic), 6.92 (d,1H, aromatic), 6.75 (d, 1H, aromatic), 6.40 (d, 1H, aromatic), 3.32 (m,2H, CH₂), 3.08 (q, 2H, CH₂), 2.40 (m, 6H, 3×CH₂), 2.30 (s, 3H, CH₃),1.67 (m, 4H 2×CH₂),

[1208] MS m/z 537 [M⁻−1].

Example 145 4-(2-Fluoro-phenyl)-3-11-[5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1209]

[1210]¹H NMR (400 MHz, DMSO-d₆) δ 13.09 (s, NH, 1H), 10.97 (s, NH, 1H),7.56 (m, 1H), 7.36 (m, 3H), 7.16 (t, J=7.8 Hz, 1H), 6.93 (d, J=7.8 Hz,1H), 6.79 (d, J =7.8 Hz, 1H), 6.40 (s, 1H), 5.86 (s, 1H), 2.66 (m, 2H),2.56 (m, 2H), 2.43 (m, 6H), 2.03 (m, 1H), 1.85 (m, 1H), 1.64 (m, 4H),1.44 (m, 3H).

[1211] MS m/z 456.2 [M⁺+].

Example 1464-(3-Fluoro-phenyl)-3-[1-[5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1212]

[1213]¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, NH, 1H), 10.99 (s, NH, 1H),7.55 (m, 1H), 7.32 (m, 1H), 7.26 (m, 2H), 7.18 (m, 1H), 6.90 (d, J=7.8Hz, 1H), 6.76 (d, J=7.4 Hz, 1H), 6.50 (s, 1H), 5.93 (s, 1H), 3.06 (m,6H), 2.68 (m, 2H), 2.51 (m, 2H), 2.06 (m, 1H), 1.84 (m, 4H), 1.62 (m,3H), 1.42 (m, 1H).

[1214] MS m/z 454 [M−1].

Example 1474-(2-Fluoro-phenyl)-3-[1-[5-(2-morpholin-4-yl-ethyl)4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-1,3-dihydroindol-2-one

[1215]

[1216]¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (s, NH, 1H), 10.99 (s, NH, 1H),7.58 (m, 1H), 7.41 (m, 3H), 7.18 (m, 1H), 6.94 (d, J=7.4 Hz, 1H), 6.80(d, J=8.2 Hz, 1H), 6.42 (s, 1H), 5.88 (s, 1H), 3.54 (m, 4H), 2.69 (m,2H), 2.56 (m, 1H), 2.32 (m, 6H), 2.04 (m, 1H), 1.85 (m, 1H), 1.66 (m,1H), 1.44 (m, 3H).

[1217] MS m/z 470 [M−1].

Example 1484-(3-Fluoro-phenyl)-3-[1-[5-(2-morpholin-4-yl-ethyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1218]

[1219]¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (s, NH, 1H), 10.96 (s, NH, 1H),7.55 (m, 1H), 7.25 (m, 3H), 7.15 (J=7.8 Hz, 1H), 6.90 (d, J=7.4 Hz, 1H),6.76 (d, J=7.4 Hz, 1H), 6.55 (s, 1H), 5.92 (s, 1H), 3.53 (m, 4H), 2.68(m, 2H), 2.56 (m, 1H), 2.31 (m, 6H), 2.04 (m, 1H), 1.85 (m, 1H), 1.64(m, 1H), 1.45 (m, 3H).

[1220] MS m/z 470 [M−1].

Example 1494-(2-Fluoro-phenyl)-3-[1-{5-[2-(4-methyl-piperazin-1-yl)-ethyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1221]

[1222] MS m/z 483 [M−1].

Example 1504-(3-Fluoro-phenyl)-3-[1-{5-[2-(4-methyl-piperazin-1-yl)-ethyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1223]

[1224] MS m/z 483 [M−1].

Example 1515-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide

[1225]

[1226]¹H NMR (400 MHz, DMSO-d₆) δ 13.48 (s, NH, 1H), 11.11 (s, NH, 1H),7.68 (m, 2H), 7.43 (m, 4H), 7.21 (t, J=7.7 Hz, 1H), 6.93 (dd, J=0.9 Hz,J=7.6 Hz, 1H), 6.79 (m, 2H), 3.21 (m, 2H), 2.45 (m, 6H), 1.84 (s, 3H),0.94 (t, J=7.4 Hz, 6H)

[1227] MS m/z 461 [M⁺+].

Example 1525-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamido-ethyl)-amide

[1228]

[1229]¹H NMR (400 MHz, DMSO-d₆) δ 13.47 (s, NH, 1H), 1 1.13 (s, NH, 1H),7.72 (m, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.58 (m, 2H), 7.53 (m, 1H), 7.41(m, 1H), 7.2 (t, J=7.7 Hz, 1H), 6.94 (dd, J=0.7 Hz, J=7.8 Hz, 11H), 6.86(s, 1H), 6.82 (dd, J=0.8 Hz, J=7.7 Hz, 1H), 3.19 (m, 2H), 2.44 (m, 6H),1.85 (s, 3H), 0.95 (t, J=7.3 Hz, 6H).

[1230] MS m/z 477 [M⁺+].

Example 1535-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid methyl-(1-methyl-piperidin-4-yl)-amide

[1231]

[1232]¹H NMR (400 MHz, DMSO-d₆) δ 13.40 (s, NH, 1H), 1 1.05 (s, NH, 1H),7.56 (m, 1H), 7.28 (m, 3H), 7.17 (t, J=7.8 Hz, 1H), 6.92 (d, J=7.4 Hz,1H), 6.78 (d, J=7.6 Hz, 1H), 6.74 (s, 1H), 3.30 (m, 4H), 2.72 (m, 4H),2.19 (s, 3H), 2.12 (br s, 3H), 1.92 (m, 1H), 1.74 (m, 2H), 1.54 (s, 3H),1.40 (m, 1H).

[1233] MS m/z 485 [M−1].

Example 1545-Methoxy-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-phenyl-1,3-dihydro-indol-2-one

[1234]

[1235] To a mixture of4-bromo-5-methoxy-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one(223 mg, 0.5 mmol) and phenylboronic acid (73 mg, 0.6 mmol) in DME/water(5 mL) were added Palladium catalyst Pd(PPh₃)₂Cl₂ (10.5 mg) and sodiumcarbonate (106 mg, 1 mmol). The system was degassed and then chargedwith nitrogen. The degas procedure was repeated for three times. Themixture was stirred under nitrogen at 85° C. oil bath for overnight. TLCshowed some de-bromination of the starting material. The degassprocedure was repeated for three more times and the heating wascontinued for 3 more days. The mixture was cooled to room temperature,the unreacted starting material was filtered off and the mother liquorwas concentrated. The residue was purified on a silica gel column togive 21 mg of5-methoxy-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-phenyl-1,3-dihydro-indol-2-one.

[1236]¹H NMR (400 MHz, DMSO-d₆) δ 13.60 (s, NH, 1H), 10.91 (s, NH, 1H),7.55 (m, 2H), 7.46 (m, 1H), 7.36 (d, J=3.5 Hz, 1H), 7.29 (m, 2H), 6.93(m, 1H), 6.86 (m, 1H), 6.43 (s, 1H), 3.62 (s, 3H), 3.53 (m, 4H), 3.44(m, 4H), 1.54 (s, 3H).

[1237] MS m/z444 [M⁺+].

Example 1555-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-1 1,2,31triazol-1-yl-propyl)-amide

[1238]

[1239]¹H NMR (400 MHz, DMSO-d₆) δ 13.51 (s, NH, 1H), 11.09 (s, NH, 1H),8.06 (d, J=0.8 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.61 (m, 2H), 7.32 (m,3H), 7.19 (t, J=7.8 Hz, 1H), 6.94 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.81 (m,2H), 5.36 (d, J=5.9 Hz, 1H), 4.47 (m, 1H), 4.26 (m, 1H), 3.96 (m, 1H),3.24 (m, 2H), 2.41 (s, 3H), 1.76 (s, 3H).

[1240] MS m/z 499 [M−1].

Example 1562-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)-amide

[1241]

[1242]¹H NMR (400 MHz, DMSO-d₆) δ 13.90 (s, NH, 1H), 1 1. 16 (s, NH,1H), 8.11 (s, 1H), 8.04 (s, 1H), 8.01 (m, 1H), 7.75 (s, 1H), 7.39 (m,1H), 7.18 (m, 3H), 7.12 (m, 1H), 6.93 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 6.77(d, J=7.8 Hz, 1H), 6.48 (m, 1H), 5.3 3 (d, J=5.5 Hz, 1H), 4.43 (m, 1H),4.22 (m, 1H), 3.90 (m, 1H), 3.19 (m, 1H), 3.08 (m, 1H), 2.32 (s, 3H).

[1243] MS m/z 485 [M−1].

Example 1572-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-[1,2,3]triazol-2-yl-propyl)-amide

[1244]

[1245]¹H NMR (400 MHz, DMSO-d₆) δ 13.88 (s, NH, 1H), 11.15 (s, NH, 1H),8.02 (s, 1H), 7.97 (s, 1H), 7.82 (s, 2H), 7.40 (m, 1H), 7.17 (m, 4H),6.93 (d, J=7.8 Hz, 1H), 6.77 (d, J=7.8HZ, 1H), 6.47 (m, 1H), 5.17 (d,J=5.9 Hz, 1H), 4.35 (m, 2H), 4.19 (m, 1H), 3.51 (m, 2H), 3.24 (m, 1H),3.10 (m, 1H), 2.32 (s, 3H).

[1246] MS m/z 485 [M−1].

Example 158 2-[4(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-morpholin-4-yl-propyl)-amide

[1247]

[1248]¹H NMR (400 MHz, DMSO-d₆) δ 13.88 (s, NH, 1H), 11.15 (s, NH, 1H),8.02 (s, 1H), 7.82 (m, 1H), 7.46 (m, 1H), 7.18 (m, 4H), 6.93 (d, J=7.0Hz, 1H), 6.77 (d, J=7.4HZ, 1H), 6.45 (m, 1H), 4.69 (m, 1H), 3.72 (m,1H), 3.60 (m, 4H), 3.24 (m, 1H), 2.95 (m, 1H), 2.50 (m, 2H), 2.45 (m,3H), 2.32 (s, 3H), 2.28 (m, 1H)

[1249] MS m/z 503 [M−1].

Example 1594-(3-Fluoro-phenyl)-3-[1-{5-methyl-3-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1250]

[1251]¹H NMR (400 MHz, DMSO-d₆) δ 13.39 (s, NH, 1H), 1 1.02 (s, NH, 1H),1H), 7.29 (m, 3H), 7.17 (t, J=7.8 Hz, 1H), 6.93 (dd, J=0.8 Hz, J=7.4 Hz,7 (m, 2H), 5.90 (m, 1H), 3.39 (m, 2H), 3.25 (m, 2H), 2.99 (s, 2H), 2.94(s, 2 (m, 4H), 2.17 (s, 3H).

[1252] MS m/z 457 [M−1].

Example 1602-{2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-N-methyl-N-(1-methyl-piperidin-4-yl)-acetamide

[1253]

[1254] MS m/z 485 [M−1].

Example 1613-[1-{3-[2-((cis)-3,5-Dimethyl-piperazin-1-yl)-2-oxo-ethyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1255]

[1256]¹H NMR (400 MHz, DMSO-d₆) δ 13.39 (s, NH, 1H), 11.07 (s, NH, 1H),7.54 (m, 1H), 7.29 (m, 3H), 7.17 (t, J=7.8 Hz, 1H), 6.93 (d, J=7.0 Hz,1H), 6.77 (m, 2H), 5.89 (d, J=2.3 Hz, 1H), 4.14 (m, 1H), 3.36 (m, 1H),2.98 (m, 2H), 2.42 (m, 4H), 2.00 (t, J=10.9 Hz, 1H), 2.29 (s, 3H), 0.92(d, J=6.3 Hz, 3H), 0.88 (d, J=5.1 Hz, 3H).

[1257] MS m/z 471 [M−1].

Example 1624-(3-Fluoro-phenyl)-3-[1l-[5-methyl-3-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrro1-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1258]

[1259]¹H NMR (400 MHz, DMSO-d₆) δ 13.41 (s, NH, 1H), l11.05 (s, NH, 1H),7.54 (m, 1H), 7.34 (m, 1H), 7.27 (m, 2H), 7.17 (t, J=7.8 Hz, 1H), 6.93(d, J=7.8 Hz, 1H), 6.77 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.75 (s, 1H), 5.92(d, J=2.3 Hz, 1H), 3.53 (m, 4H), 3.39 (m, 2H), 3.34 (m, 4H), 3.01 (s,2H), 2.29 (s, 3H).

[1260] MS m/z 444 [M−1 ].

Example 1634-(3-Fluoro-phenyl)-3-[1-5-methyl-3-[2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1261]

[1262]¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, NH, 1H), 11.00 (s, NH, 1H),7.52 (m, 1H), 7.32 (m, 1H), 7.26 (m, 2H), 7.15 (t, J=7.8 Hz, 1H), 6.91(dd, J=1.2 Hz, J=7.8 Hz, 1H), 6.76 (m, 2H), 5.88 (d, J=2.3 Hz, 1H), 4.07(m, 1H), 3.49 (m, 1H), 2.97 (m, 3H), 2.70 (m, 1H), 2.42 (m, 4H), 2.27(s, 3H), 2.14 (m, 1H), 1.75 (m, 2H), 1.64 (m, 4H), 1.18 (m, 2H).

[1263] MS m/z 511 [M−1].

Example 1644-(3-Fluoro-phenyl)-3-[1-{5-methyl-3-[2-oxo-2-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1264]

[1265]¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, NH, 1H), 1 1.00 (s, NH, 1H),7.52 (m, 1H), 7.24 (m, 3H), 7.14 (t, J=7.8 Hz, 1H), 6.91 (d, J=7.0 Hz,1H), 6.76 (m, 2H), 5.88 (d, J=2.3 Hz, 1H), 3.99 (m, 1H), 3.21 (m, 2H),2.90 (m, 2H), 2.55 (m, 2H), 2.40 (m, 4H), 2.31 (s, 3H), 1.86 (m, 4H),1.62 (m, 4H).

[1266] MS m/z511 [M−1]

Example 1652-{2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-N-(2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)-acetamide

[1267]

[1268]¹H NMR (400 MHz, DMSO-d₆) δ 13.35 (s, NH, 1H), l 1.00 (s, NH, 1H),8.03 (d, J=0.8 Hz, 1H), 7.82 (m, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.50 (m,1H), 7.26 (m, 3H), 7.17 (t, J=7.8 Hz, 1H), 6.93 (dd, J=1.2 Hz, J=7.8 Hz,1H), 6.78 (m, 2H), 5.96 (d, J=2.3 Hz, 1H), 5.34 (d, J=5.4 Hz, 1H), 4.40(m, 1H), 4.21 (m, 1H), 3.86 (m, 1H), 3.08 (m, 2H), 2.82 (s, 2H), 2.29(s, 3H).

[1269] MS m/z 499 [M−1].

Example 166-{2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-acetamide

[1270]

[1271]¹H NMR (400 MHz, DMSO-d₆) δ 13.34 (s, NH, 1H), l 1.00 (s, NH, 1H),7.53 (m, 2H), 7.25 (m, 3H), 7.17 (t, J=7.4 Hz, 1H), 6.94 (dd, J=0.8 Hz,J=7.8 Hz, 1H), 6.79 (m, 2H), 5.93 (d, J=2.3 Hz, 1H), 3.11 (m, 2H), 2.76(s, 2H), 2.42 (m, 6H), 2.28 (s, 3H), 1.66 (m, 4H).

[1272] MS m/z 471 [M−1].

Example 1672-{2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-acetamide

[1273]

[1274]¹H NMR (400 MHz, DMSO-d₆) δ 13.34 (s, NH, 1H), 11.01 (s, NH, 1H),7.58 (m, 1H), 7.51 (m, 1H), 7.25 (m, 3H), 7.17 (t, J=7.8 Hz, 1H), 6.93(d, J=7.8 Hz, 1H), 6.79 (m, 2H), 5.91 (d, J=2.3 Hz, l H), 3.20 (m, 2H),2.74 (s, 2H), 2.37 (m, 5H), 2.28 (s, 3H), 1.64 (m, 3H) 1.53 (m, 2H).

[1275] MS m/z 485 [M−1].

Example 168N-(2,4-Dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylmethyl)-2-{2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-acetamide

[1276]

[1277]¹H NMR (400 MHz, DMSO -d₆) δ 13.38 (s, NH, 1H), 11.02 (s, NH, 1H),10.93 (s, 2H), 8.07 (m, 1H), 7.48 (m, 1H), 7.24 (m, 3H), 7.17 (t, J=7.4Hz, 1H), 6.94 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.78 (m, 2H), 5.96 (d, J=2.3Hz, 1H), 5.18 (s, 1H), 3.89 (d, J=5.5 Hz, 2H), 2.86 (s, 2H), 2.29 (s,3H).

[1278] MS m/z 498 [M−1].

Example 1694-(2-Fluoro-phenyl)-3-[1-5-methyl-3-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1279]

[1280]¹H NMR (400 MHz, DMSO-d₆) δ 13.42 (s, NH, 1H), 1 1.02 (s, NH, 1H),7.56 (m, 1H), 7.45 (m, 1H), 7.36 (m, 2H), 7.19 (t, J=7.4 Hz, 1H), 6.95(d, J=7.8 Hz, 1H), 6.80 (d, J=7.4 Hz, 1H), 6.59 (d, J=1.2 Hz, 1H), 5.89(d, J=2.3 Hz, 1H), 3.39 (m, 2H), 3.24 (m, 2H), 2.94 (m, 2H), 2.29 (s,3H), 2.22 (m, 4H), 2.18 (s, 3H).

[1281] MS m/z 457 [M−1].

Example 1702-{2-]4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-N-methyl-N-(1-methyl-piperidin4-yl)-acetamide

[1282]

[1283] MS m/z 485 [M−1].

Example 1713-[1-{3-[2-((cis)-3,5-Dimethyl-piperazin-1-yl)-2-oxo-ethyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1284]

[1285]¹H NMR (400 MHz, DMSO-d₆) δ 13.41 (s, NH, 1H), 1 1.04 (s, NH, 1H),7.54 (m, 1H), 7.44 (m, 1H), 7.36 (m, 2H), 7.19 (t, J=7.4 Hz, 1H), 6.96(dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.81 (d, J=7.4 Hz, 1H), 6.62 (s, 1H), 5.88(d, J=2.0 Hz, 1H), 4.16 (m, 1H), 3.38 (m, 1H), 2.95 (m, 2H), 2.45 (m,1H), 2.29 (s, 3H), 2.00 (t, J=10.7 Hz, 1H), 0.95 (d, J=6.3 Hz, 3H), 0.88(d, J=6.3 Hz, 3H).

[1286] MS m/z 471 [M−1].

Example 1724-(2-Fluoro-phenyl)-3-[1-[5-methyl-3-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1287]

[1288]¹H NMR (400 MHz, DMSO-d₆) δ 13.42 (s, NH, 1H), 11.03 (s, NH, 1H),7.56 (m, 1H), 7.44 (m, 1H), 7.36 (m, 2H), 7.19 (t, J=7.8 Hz, 1H), 6.96(dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.81 (d, J=7.4 Hz, 1H), 6.59 (s, 1H), 5.92(d, J=2.3 Hz, 1H), 3.53 (m, 4H) 3.39 (m, 2H), 3.27 (m, 2H), 2.95 (m,2H), 2.29 (s, 3H).

[1289] MS m/z 444 [M−1].

Example 1734-(2-Fluoro-phenyl)-3-[1-{5-methyl-3-[2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1290]

[1291]¹H NMR (400 MHz, DMSO-d₆) δ 13.41 (s, NH, 1H), 11.05 (s, NH, 1H),7.56 (m, 1H), 7.46 (m, 1H), 7.35 (m, 2H), 7.19 (t, J=7.8 Hz, 1H), 6.96(dd, J=6.6 Hz, 1H), 6.80 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.60 (s, 1H),5.89 (d, J=2.0 Hz, 1H), 4.11 (m, 1H), 3.48 (m, 1H), 3.34 (m, 4H), 2.42(m, 3H), 2.71 (m, 1H), 2.29 (s, 3H), 2.42 (m, 1H), 1.78 (m, 2H), 1.67(m, 4H), 1.21 (m, 2H).

[1292] MS m/z 51 1 [M−1].

Example 1744-(4-Chloro-phenyl)-3-[1-{3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1293]

[1294]¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, NH, 1H), 10.89 (s, NH, 1H),7.60 (d, J=8.9 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.13 (t, J=7.6 Hz, 1H),6.91 (d, J=7.4 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.64 (s, 1H), 3.39 (m,4H), 2.54 (m, 4H), 2.36 (m, 4H), 2.24 (s, 3H), 2.19 (s, 3H), 1.59 (s,3H).

[1295] MS m/z 503 [M−1].

Example 1754-(4-Chloro-phenyl)-3-[1-{4-[3-((cis)-3,5-dimethyl-piperazin-1-yl)-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1296]

[1297]¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (s, NH, 1H), 10.89 (s, NH, 1H),7.59 (d, J=8.8 Hz, 2H), 7.42 (d, J=7.8 Hz, 2H), 7.13 (t, J=7.8 Hz, 1H),6.91 (d, J=8.0 Hz, 1H), 6.75 (d, J=7.4 Hz, 1H), 6.64 (s, 1H), 4.22 (d,J=12.0 Hz, 1H), 3.49 (d, J=10.4 Hz, 1H), 2.53 (m, 2H), 2.32 (m, 5H),2.23 (s, 3H), 2.15 (m, 1H), 1.92 (t, J=1.6 Hz, 1H), 1.60 (s, 3H), 0.93(d, J=6.3 Hz, 3H), 0.85 (d, J=5.6 Hz, 3H).

[1298] MS m/z 517 [M−1].

Example 1763-[1-{3,5-Dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1299]

[1300]¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (s, NH, 1H), 10.89 (s, NH, 1H),7.44 (m, 2H), 7.37 (m, H), 7.13 (t, J=7.5 Hz, 1H), 6.90 (d, J=7.4 Hz,1H), 6.75 (d, J=8.0 Hz, 1H), 6.68 (s, 1H), 3.38 (m, 2H), 3.28 (m, 2H),2.53 (m, 2H), 2.33 (t, J=7.4 Hz, 2H), 2.24 (s, 3H), 2.17 (m, 2H), 2.10(m, 5H), 1.60 (s, 3H).

[1301] MS m/z 487 [M⁺+].

Example 1775-[4-[3-(2-Hydroxy-ethyl)-phenyl]-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1302]

[1303]¹H NMR (400 MHz, DMSO-d₆) δ 13.42 (s, 1H, NH), 11.03 (s, 1H, NH),7.45 (m, 2H), 7.35 (d, 1H), 7.26 (s, 1H), 7.20 (d, 1H), 7.15 (t, 1H),6.89 (d, 1H), 6.75 (d, 1H), 6.74 (s, 1H), 4.66 (t, 1H), 3.61 (m, 2H),3.28 (m, 2H), 2.79 (m, 2H), 2.54 (m, 6H), 2.36 (s, 3H), 1.68 (m, 4H),1.64 (s, 3H).

[1304] MS m/z 497 [M−1].

Example 1785-[4-[3-(2-Hydroxy-ethyl)-phenyl]-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[1305]

[1306]¹H NMR (400 MHz, DMSO-d₆) δ 13.45 (s, NH, 1H), 11.01 (s, NH, 1H),8.08 (s, 1H), 7.69 (s, 1H), 7.59 (t, J=5.9 Hz, 1H), 7.42 (t, J=7.6 Hz,1H), 7.31 (d, J=7.8 Hz, 1H), 7.24 (s, 1H), 7.19 (d, J=7.4 Hz, 1H), 7.15(t, J=7.8 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.75 (d, J=7.4 Hz, 1H), 6.72(s, 1H), 4.66 (t, J=5.1 Hz, 1H), 4.50 (t, J=5.8 Hz, 2H), 3.60 (m, 4H),2.76 (t, J=7.0 Hz, 2H), 2.25 (s, 3H), 1.54 (s, 3H).

[1307] MS n/z 495 [M−1].

Example 1792-]4-[3-(2-Hydroxy-ethyl)-phenyl]-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide

[1308]

[1309]¹H NMR (400 MHz, DMSO-d₆) δ 13.79 (s, 1H, NH), 11.10 (s, 1H, NH),8.05 (t, 1H), 7.98 (s, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.29 (t, 1H),7.23 (d, 1H), 7.21 (s, 1H), 7.17 (t, 1H), 7.12 (d, 1H), 6.88 (d, 1H),6.73 (d, 1H), 6.29 (s, 1H), 4.51 (t, 1H), 4.44 (t, 2H), 3.63 (dd, 2H),3.42 (m, 2H), 2.74 (t, 2H), 2.26 (s, 3H).

[1310] MS m/z 481 [M−1].

Example 180 3-[1-[3,5-Dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one

[1311]

[1312]¹H NMR (400 MHz, DMSO-d₆) δ 13.41 (s, NH, 1H), 11.00 (s, NH, 1H),7.43 (t, 1H), 7.15 (t, 1H), 7.02 (d, 1H), 6.96 (m, 2H), 6.89 (d, 1H),6.82 (s, 1H), 6.77 (d, 1H), 4.20 (m, 1H), 3.74 (s, 3H), 3.60 (m, 1H),2.92 (m, 2H), 2.43 (m, 4H), 2.21 (s, 3H), 1.78 (m, 2H), 1.63 (m, 4H),1.55 (s, 3H), 1.22 (m, 3H).

[1313] MS m/z 523 [M−1].

Example 1814-(2-Chloro-phenyl)-3-[l1-3,5-dimethyl4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1314]

[1315]¹H NMR (400 MHz, DMSO-d₆) δ 13.40 (s, NH, 1H), 10.50 (br s, NH,1H), 7.66 (m, 1H), 7.51 (m, 2H), 7.43 (m, 1H), 7.19 (t, 1H), 6.94 (d,1H), 6.74 (d, 1H), 6.38 (s, 1H), 4.20 (m, 1H), 3.60 (m, 1H), 2.92 (m,2H), 2.43 (m, 4H), 2.21 (s, 3H), 1.78 (m, 2H), 1.63 (m, 4H), 1.55 (s,3H), 1.22 (m, 3H).

[1316] MS m/z 528 [M−1].

Example 1824-(4-Chloro-phenyl)-3-[1-[3,5-dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1317]

[1318]¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, NH, 1H), 11.02 (s, NH, 1H),7.59 (d, 2H), 7.43 (d, 2H), 7.17 (t, 1H), 6.91 (d, 1H), 6.77 (d, 1H),6.63 (s, 1H), 4.20 (m, 1H), 3.40. (m, 1H), 2.92 (m, 2H), 2.44 (m, 4H),2.21 (s, 3H), 2.85 (m, 1H), 1.77 (m, 2H), 1.64 (m, 5H), 1.53 (s, 3H),1.22 (m, 1H).

[1319] MS m/z 528 [M−1].

Example 1834-(3-Chloro-phenyl)-3-[1-[3,5-dimethyl4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1320]

[1321]¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, NH, 1H), 10.50 (br s, NH,1H), 7.52 (m, 2H), 7.39 (m, 1H), 7.17 (t, J=7.8 Hz, 1H), 7.04 (t, J=8.2Hz, 1H), 6.92 (m, 1H), 6.78 (d, J=7.4 Hz, 1H), 6.74 (s, 1H), 4.20 (m,1H), 3.40 (m, 1H), 2.92 (m, 2H), 2.44 (m, 4H), 2.21 (s, 3H), 2.85 (m,1H), 1.77 (m, 2H), 1.64 (m, 5H), 1.53 (s, 3H), 1.22 (m, 1H).

[1322] MS m/z 528 [M⁻−1].

Example 1843-[1-[3,5-Dimethyl4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1323]

[1324]¹H NMR (400 MHz, DMSO-d6) δ 13.41 (s, NH, 1H), 11.05 (s, NH, 1H),7.57 (m, 1H), 7.28 (m, 3H), 7.17 (t, 1H), 6.92 (d, 1H), 6.78 (d, 1H),6.74 (s, 1H), 4.15 (m, 1H), 3.49 (m, 1H), 2.93 (m, 2H), 2.43 (m, 4H),2.21 (s, 3H), 2.14 (m, 1H), 1.77 (m, 2H), 1.63 (m, 5H), 1.56 (s, 3H),1.22 (m, 1H).

[1325] MS m/z 511 [M−1].

Example 1853-[1-[5-Methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-phenyl-1,3-dihydro-indol-2-one

[1326]

[1327]¹H NMR (400 MHz, DMSO-d₆) δ 13.65 (s, NH, 1H), 11.12 (s, NH, 1H),7.43 (m, 3H), 7.37 (m, 2H), 7.20 (t, J=7.8 Hz, 1H), 6.95 (s, 1H), 6.92(d, J=7.8 Hz, 1H), 6.76 (d, J=7.4 Hz, 1H), 6.06 (d, J=2.3 Hz, 1H), 4.05(m, 1H), 3.45 (m, 1H), 2.87 (m, 2H), 2.45 (m, 4H), 2.35 (s, 3H), 2.20(m, 1H), 1.85 (m, 1H), 1.65 (m, 5H), 1.30 (m, 1H), 1.15 (m, 1H).

[1328] MS m/z 479 [M−1].

Example 1864-(4-Chloro-phenyl)-3-[1-[5-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1329]

[1330]¹H NMR (400 MHz, DMSO-d₆) δ 13.67 (s, NH, 1H), 1 1.15 (s, NH, 1H),7.49 (d, 2H), 7.40 (d, 2H), 7.21 (t, 1H), 7.06 (s, 1H), 6.94 (d, 1H),6.74 (d, 1H), 6.10 (s, 1H), 4.11 (m, 1H), 3.55 (m, 1H), 2.87 (m, 2H),2.47 (m, 4H), 2.34 (s, 3H), 2.21 (m, 1H), 1.82 (m, 1H), 1.69 (m, 5H),1.30 (m, 1H)1.20 (m, 1H).

[1331] MS m/z 514 [M−1].

Example 1874-(3-Fluoro-phenyl)-3-[1-[5-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1332]

[1333]¹H NMR (400 MHz, DMSO-d₆) δ 13.60 (s, NH, 1H), 1 1.12 (s, NH, 1H),7.48 (m, 1H), 7.23 (m, 4H), 6.95 (d, 1H), 6.94 (s, 1H), 6.78 (d, 1H),6.09 (d, 1H), 4.08 (m, 1H), 3.52 (m, 1H), 2.81 (m, 2H), 2.47 (m, 4H),2.32 (s, 3H), 2.18 (m, 1H), 1.82 (m, 1H), 1.67 (m, 5H), 1.21 (m, 2H).

[1334] MS m/z 497 [M−1].

Example 1883-[1-[5-Methyl-3-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-phenyl-1,3-dihydro-indol-2-one

[1335]

[1336]¹H NMR (400 MHz, DMSO-d₆) δ 13.63 (s, NH, 1H), 11.10 (s, NH, 1H),7.39 (m, 5H), 7.18 (t, J=7.6 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J=6.6,1H),6.73 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.06 (d, J=2.3 Hz, 1H), 3.52 (m, 2H),3.35 (m, 4H), 3.18 (m, 2H), 2.26 (s, 3H).

[1337] MS m/z 412 [M−1].

Example 1894-(2-Chloro-phenyl)-3-[1-[5-methyl-3-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1338]

[1339]¹H NMR (400 MHz, DMSO-d₆) δ 13.65 (s, NH, 1H), 11.15 (s, NH, 1H),7.54 (dd, J=1.6 Hz, J=8.2 Hz, 1H), 7.44 (m, 2H), 3.33 (dd, J=2.0 Hz,J=7.0 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 6.95 (dd, J=0.8 Hz, J=7.8 Hz,1H), 6.69 (d, J 7.8 Hz, 1H), 6.57 (s, 1H), 6.07 (d, J=2.7 Hz, 1H), 3.58(m, 2H), 3.44 (m, 4H), 3.22 (m, 2H), 2.31 (s, 3H).

[1340] MS m/z 446 [M−1].

Example 1904-(4-Chloro-phenyl)-3-[1-[5-methyl-3-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1341]

[1342]¹H NMR (400 MHz, DMSO-d₆) δ 13.67 (s, NH, 1H), 11.14 (s, NH, 1H),7.48 (dd, J=2.0 Hz, J=6.6 Hz, 2H), 7.38 (dd, J=2.0 Hz, J=6.6 Hz, 2H),7.19 (t, J=7.6 Hz, 1H), 7.07 (s, 1H), 6.91 (dd, J=0.8 Hz, J=7.8 Hz, 1H),6.73 (d, J=7.4 Hz, 1H), 6.10 (d, J=2.3 Hz, 1H), 3.54 (m, 2H), 3.42 (m,4H), 3.27 (m, 2H), 2.31 (s, 3H).

[1343] MS m/z446 [M−1].

Example 1914-(3-Fluoro-phenyl)-3-[1-[5-methyl-3-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1344]

[1345]¹H NMR (400 MHz, DMSO-d₆) δ 13.62 (s, NH, 1H), 11.12 (s, NH, 1H),7.48 (m, 1H), 7.21 (m, 2H), 7.18 (dd, J=1.6 Hz, J=7.0 Hz, 2H), 6.96 (s,1H), 6.92 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 6.76 (dd, J=0.8 Hz, J=7.4 Hz,1H), 6.09 (d, J=2.3 Hz, 1H), 3.54 (m, 2H), 3.40 (m, 4H), 3.28 (m, 2H),2.30 (s, 3H).

[1346] MS m/z 430 [M−1].

Example 1922-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-ylmethyl)-amide

[1347]

[1348]¹H NMR (400 MHz, DMSO-d₆) δ 13.82 (s, NH, 1H), 11.15 (s, NH, 1H),10.99 (s, 1H), 10.85 (s, 1H), 8.31 (br t, 1H), 7.92 (s, 1H), 7.34 (m,3H), 7.27 (m, 1H), 7.19 (t, J=7.8 Hz, 1H), 6.91 (d, J=7.4 Hz, 1H), 6.76(d, J=7.4 Hz, 1H), 6.45 (s, 1H), 5.20 (s, 1H), 3.94 (br d, 2H), 2.31 (s,3H).

[1349] MS m/z 500 [M−1].

Example 1934-(3-Chloro-phenyl)-3-[1-[3-methyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1350]

[1351]¹H NMR (400 MHz, DMSO-d₆) δ 13.48 (s, NH, 1H), 1 1.18 (s, NH, 1H),7.56 (m, 2H), 7.52 (m, 1H), 7.40 (m, 1H), 7.37 (d, J=3.1 Hz, 1H), 7.21(t, J=7.8 Hz, 1H), 6.93 (dd, J=0.8 Hz, J=7.4 Hz, 1H), 6.81 (s, 1H), 6.80(d, J=7.4 Hz, 1H), 3.90 (br m, 2H), 2.94 (m, 2H), 2.44 (m, 4H), 2.16 (m,1H), 1.78 (m, 2H), 1.65 (s, 3H), 1.64 (m, 4H), 1.26 (m, 2H).

[1352] MS m/z 513 [M−1].

Example 1944-(3-Chloro-phenyl)-3-[1-[3-methyl-4-(2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1353]

[1354]¹H NMR (400 MHz, DMSO-d₆) δ 13.45 (s, NH, 1H), 11.13 (s, NH, 1H),7.57 (d, J=2.3 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H), 7.52 (m, 2H), 7.40 (m,1H), 7.21 (t, J=7.6 Hz, 1H), 6.93 (dd, J=0.8 Hz, J=7.0 Hz, 1H), 6.83 (s,1H), 6.80 (d, J=7.4 Hz, 1H), 4.19 (m, 1H), 3.41 (m, 2H), 2.55 (m, 2H),2.43 (m, 4H), 1.86 (m, 4H), 1.70 (s, 3H), 1.63 (m, 4H).

[1355] MS m/z 514 [M−1].

Example 1955-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]4-methyl-1H-pyrrole-3-carboxylicacid (2-morpholin-4-yl-ethyl)-amide

[1356]

[1357]¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, NH, 1H), 1 1.12 (s, NH, 1H),7.56 (t, J=5.6 Hz, 1H), 7.67 (d, J=3.1 Hz, 1H), 7.58 (d, J=3.1 Hz, 1H),7.57 (d, J=0.8 Hz, 1H), 7.52 (s, 1H), 7.40 (m, 1H), 7.21 (t, J=7.6 Hz,1H), 6.93 (d, J =7.8 Hz, 1H), 6.85 (s, 1H), 6.80 (d, J=7.8 Hz, 1H), 3.54(m, 4H), 3.26 (m, 4H), 2.37 (m, 4H), 1.84 (s, 3H).

[1358] MS m/z 489 [M−1].

Example 1965-]4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]4-methyl-1H-pyrrole-3-carboxylicacid 13-(2-methyl-piperidin-1-yl)-propyl]-amide

[1359]

[1360]¹H NMR (400 MHz, DMSO-d₆) δ 13.45 (s, NH, 1H), 11.13 (s, NH, 1H),7.56 (m, 1H), 7.67 (d, J=3.1 Hz, 1H), 7.58 (d, J=2.3 Hz, 1H), 7.57 (d,J=0.8 Hz, 1H), 7.52 (s, 1H), 7.40 (m, 1H), 7.21 (t, J=7.8 Hz, 1H), 6.93(d, J=7.8 Hz, 1H), 6.85 (s, 1H), 6.80 (d, J=7.4 Hz, 1H), 3.32 (m, 2H),3.12 (m, 2H), 2.71 (m, 2H), 2.26 (m, 2H), 1.83 (s, 3H), 1.56 (m, 4H),1.41 (m, 1H), 1.20 (m, 2H), 0.96 (d, J=5.9 Hz, 3H).

[1361] MS m/z 516 [M−1].

Example 1975-]4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-piperidin-1-yl-ethyl)-amide

[1362]

[1363]¹H NMR (400 MHz, DMSO-d₆) δ 13.5 1 (s, NH, 1H), 1 1.1 5 (s, NH,1H), 8.27 (m, 1H), 7.82 (d, J=3.1 Hz, 1H), 7.58 (d, J=3.1 Hz, 1H), 7.57(d, J=1.2 Hz, 1H), 7.52 (s, 1H), 7.40 (m, 1H), 7.22 (t, J=7.8 Hz, 1H),6.93 (d, J=7.8 Hz, 1H), 6.85 (s, 1H), 6.81 (d, J=7.8 Hz, 1H), 3.51 (m,4H), 3.12 (m, 2H), 2.87 (m, 2H), 1.86 (s, 3H), 1.72 (m, 5H), 1.36 (m,1H).

[1364] MS m/z488 [M−1].

Example 1985-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-pyridin-4-yl-ethyl)-amide

[1365]

[1366]¹H NMR (400 MHz, DMSO-d₆) δ 13.45 (s, NH, 1H), 11.11 (s, NH, 1H),8.43 (m, 2H), 7.96 (t, J=5.5 Hz, 1H), 7.64 (d, J=3.5 Hz, 1H), 7.57 (dd,J=1.7 Hz, J=4.3 Hz, 2H), 7.52 (s, 1H), 7.40 (m, 1H), 7.21 (m, 3H), 6.93(d, J=7.8 Hz, 1H), 6.84 (s, 1H), 6.80 (d, J 7.8 Hz, 1H), 3.40 (m, 2H),2.78 (t, J=7.2 Hz, 2H), 1.81 (s, 3H).

[1367] MS m/z 481 [M−1].

Example 1995-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1368]

[1369]¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, NH, 1H), 1 1.12 (s, NH, 1H),7.83 (t, J=5.9 Hz, 1H), 7.69 (d, J=3.5 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H),7.57 (d, J=1.2 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.40 (m, 1H), 7.21 (t,J=7.8 Hz, 1H), 6.93 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.85 (s, 1H), 6.80(dd, J=0.8 Hz, J=7.4 Hz, 1H), 3.26 (m, 2H), 2.50 (m, 6H), 1.84 (s, 3H),1.67 (m, 4H).

[1370] MS m/z 473 [M−1].

Example 2005-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

[1371]

[1372]¹H NMR (400 MHz, DMSO-d₆) δ 13.44 (s, NH, 1H), 11.12 (s, NH, 1H),7.82 (br t, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.58 (m, 2H), 7.52 (d, J=1.2Hz, 1H), 7.40 (m, 1H), 7.21 (t, J=7.8 Hz, 1H), 6.93 (dd, J=0.8 Hz, J=7.8Hz, 1H), 6.85 (s, 1H), 6.80 (d, J=7.4 Hz, 1H), 3.31 (m, 2H), 3.17 (t,J=7.2 Hz, 2H), 3.10 (m, 2H), 2.19 (t, J=8.0 Hz, 2H), 1.89 (m, 2H), 1.84(s, 3H), 1.62 (m, 2H).

[1373] MS m/z 501 [M−1].

Example 2015-]4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-morpholin-4-yl-propyl)-amide

[1374]

[1375]¹H NMR (400 MHz, DMSO-d6) δ 13.47 (s, NH, 1H), 11.13 (s, NH, 1H),7.80 (d, J=5.5 Hz, 1H), 7.72 (m, 1H), 7.57 (m, 2H), 7.53 (m, 1H), 7.40(m, 1H), 7.21 (m, 1H), 6.94 (t, J=6.4 Hz, 1H), 6.85 (d, J=5.1 Hz, 1H),6.81 (t, J=6.3 Hz, 1H), 4.73 (m, 1H), 3.73 (m, 1H), 3.32 (d, J=5.1 Hz,2H), 3.28 (m, 1H), 3.04 (m, 1H), 2.58 (m, 2H), 2.38 (m, 4H), 2.25 (m,2H), 1.84 (m, 3H).

[1376] MS m/z 519 [M−1].

Example 2025-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]4-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)-amide

[1377]

[1378]¹H NMR (400 MHz, DMSO-d6) δ 13.46 (s, NH, 1H), 11.12 (s, NH, 1H),8.05 (s, 1H), 7.97 (t, J=5.7 Hz, 1H), 7.75 (d, J=3.1 Hz, 1H), 7.68 (s,1H), 7.58 (m, 2H), 7.52 (m, 1H), 7.40 (m, 1H), 7.21 (t, J=7.8 Hz, l H),6.93 (d, J=7.8 Hz, 1H), 6.86 (s, 1H), 6.80 (d, J=7.4 Hz, 1H), 3.36 (d,J=5.5 Hz, 1H), 4.45 (dd, J=3.5 Hz, J=14.5 Hz, 1H), 4.23 (dd, J=7.2 Hz,J=14.1 Hz, 1H), 3.95 (m, 1H), 3.24 (t, J=6.0 Hz, 1H), 3.20 (t, J=6.0 Hz,1H), 1.86 (s, 3H).

[1379] MS m/z 501 [M−1].

Example 2033-[1-{3,5-Dimethyl4-[2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1380]

[1381]¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, NH, 1H), 10.93 (s, NH, 1H),7.52 (m, 1H), 7.40 (m, 3H), 7.13 (t, J=7.8 Hz, 1H), 6.92 (dd, J=0.78 Hz,J=7.8 Hz, 1H), 6.77 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 6.58 (s, 1H), 4.10 (d, J=14.1 Hz, 1H), 3.79 (d, j=12.19 Hz, 1H), 3.36 (m, 2H), 3.01 (t,J=11.8 Hz, 1H), 2.67 (t, J=11.1 Hz, 1H), 2.42 (m, 4H), 2.17 (s, 3H),2.12 (m, 1H), 1.75 (d, J=1.7 Hz, 2H), 1.62 (m, 4H), 1.45 (s, 3H), 1.16(m, 2H).

[1382] MS m/z 525 [M−1].

Example 2043-[1-{3,5-Dimethyl4-[2-oxo-2-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1383]

[1384]¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, NH, 1H), 10.93 (s, NH, 1H),7.52 (m, 1H), 7.40 (m, 3H), 7.13 (t, J=7.8 Hz, 1H), 6.92 (dd, J=0.78 Hz,J=7.8 Hz, 1H), 6.77 (dd, J=0.8 Hz, J=7.4 Hz, 1H), 6.58 (s, 1H), 4.05 (m,1H), 3.42 (m, 2H), 3.27 (m, 2H), 2.44 (m, 2H), 2.37 (m, 4H), 2.17 (s,3H), 1.84 (m, 4H), 1.62 (m, 4H), 1.46 (s, 3H).

[1385] MS m/z 525 [M−1].

Example 2052-{5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-N-(2-morpholin-4-yl-ethyl)-acetamide

[1386]

[1387]¹H NMR (400 MHz, DMSO-d₆) δ 13.31 (s, NH, 1H), 10.93 (s, NH, 1H),7.51 (m, 2H), 7.40 (m, 3H), 7.14 (t, J=7.6 Hz, 1H), 6.92 (d, J=7.8 Hz,1H), 6.77 (d, J=7.4 Hz, 1H), 6.59 (s, 1H), 3.47 (m, 4H), 3.11 (s, 2H),3.07 (m, 2H), 2.27 (m, 6H), 2.22 (s, 3H), 1.52 (s, 3H).

[1388] MS m/z 501 [M−1].

Example 2063-1-]4-[2-((cis)-3,5-Dimethyl-piperazin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]4-(2-fluoro-phenyl)-1,3-dihydroindol-2-one

[1389]

[1390]¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, NH, 1H), 10.96 (s, NE, 1H),7.51 (m, 1H), 7.40 (m, 3H), 7.14 (t, J=7.8 Hz, 1H), 6.92 (d, J=0.8 Hz,J=7.8 Hz, 1H), 6.77 (d, J=0.8 Hz, J=8.6 Hz, 1H), 6.58 (s, 1H), 4.15 (d,J=12.1 Hz, 1H), 3.71 (t, J=8.2 Hz, 1H), 3.28 (m, 2H), 2.43 (m, 4H), 2.17(s, 3H), 1.96 (t, J=1.5 Hz, 1H), 1.45 (s, 3H), 0. 89 (d, J=6.6 Hz, 6H).

Example 2072-{5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-N-(2-piperidin-1-yl-ethyl)-acetamide

[1391]

[1392]¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (s, NH, 1H), 10.94 (s, NH, 1H),7.52 (m, 1H), 7.39 (m, 4H), 7.14 (t, J=7.6 Hz, 1H), 6.92 (d, J=7.0 Hz,1H), 6.77 (d, J=7.4 Hz, 1H), 6.60 (s, 1H), 3.11 (s, 2H), 3.06 (m, 2H),2.24 (m, 6H), 2.21 (s, 3H), 1.51 (s, 3H), 1.38 (m, 4H), 1.30 (m, 2H).

[1393] MS m/z 499 [M−1].

Example 2082-{5-]4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-N-(2-pyridin-4-yl-ethyl)-acetamide

[1394]

[1395]¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, NH, 1H), 10.93 (s, NH, 1H),8.40 (m, 2H), 7.72 (t, J=5.5 Hz, 1H), 7.55 (m, 1H), 7.40 (m, 3H), 7.14(m, 3H), 6.92 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.77 (dd, J=0.8 Hz, J=8.6Hz, 6.58 (s, 1H), 3.25 (m, 2H), 3.08 (s, 2H), 2.68 (m, 2H), 2.16 (s,3H), 1.43 (s, 3H).

[1396] MS m/z 493 [M−1].

Example 2092-{5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-acetamide

[1397]

[1398]¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (s, NH, 1H), 10.93 (s, NH, 1H),7.60 (t, J=5.5 Hz, 1H), 7.53 (m, 1H), 7.42 (t, J=7.4 Hz, 1H), 7.37 (d,J=7.4 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.92 (dd,J=0.8 Hz, J=7.8 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.60 (s, 1H), 3.11 (s,2H), 3.07 (m, 2H), 2.37 (m, 6H), 2.21 (s, 3H), 1.61 (m, 4H), 1.50 (s,3H).

[1399] MS m/z 485 [M−1].

Example 2103-[1-{3,5-Dimethyl-4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrrol-2-yl]-meth-(Z)-ylidene]4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1400]

[1401]¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, NH, 1H), 10.94 (s, NH, 1H),7.52 (m, 1H), 7.42 (m, 3H), 7.14 (t, J=7.8 Hz, 1H), 6.92 (dd, J=1.0 Hz,J=7.4 Hz, 1H), 6.77 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.58 (s, 1H), 3.40 (m,4H), 3.31 (s, 2H), 1.20 (m, 4H), 2.16 (s, 3H), 2.13 (s, 3H), 1.45 (s,3H).

[1402] MS m/z 471 [M−1].

Example 2113-[1-[3,5-Dimethyl4-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1403]

[1404]¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (s, NH, 1H), 10.95 (s, NH, 1H),7.51 (m, l H), 7.40 (m, 3H), 7.14 (t, J=7.8 Hz, 1H), 6.92 (dd, J=0.8 Hz,J=7.8 Hz, 1H), 6.77 (dd, J=1.0 Hz, J=7.4 Hz, 1H), 6.59 (s, 1H), 3.50 (m,4H), 3.46 (m, 2H), 3.31 (m, 4H), 2.17 (s, 3H), 1.45 (s, 3H).

[1405] MS m/z 458 [M−1].

Example 212N-(2-Diethylamino-ethyl)-2-{5-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetamide

[1406]

[1407]¹H NMR (400 MHz, DMSO-d₆) δ 13.31 (s, NH, 1H), 10.93 (s, NH, 1H),7.53 (m, 1H), 7.40 (m, 4H), 7.14 (t, J=7.8 Hz, 1H), 6.92 (d, J=7.8 Hz,1H), 6.77 (d, J=7.4 Hz, 1H), 6.59 (s, 1H), 3.11 (s, 2H), 3.03 (m, 2H),2.40 (m, 6H), 2.21 (s, 3H), 1.50 (s, 3H), 0.87 (t, J=7.0 Hz, 6H).

[1408] MS m/z 487 [M−1].

Example 2134-(2-Chloro-phenyl)-3-[1-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1409]

[1410]¹H NMR (400 MHz, DMSO-d₆) 513.41 (s, 1H, NH), 11.04 (s, 1H, NH),7.64 (m, 1H), 7.5 (m, 2H), 7.41 (m, 1H), 7.18 (t, J=8.7 Hz, 1H), 6.93(dd, J=0.9 Hz, J=9.1 Hz, 1H), 6.73 (dd, J=1.1 Hz, J=9.1 Hz, 1H), 6.37(s, 1H), 3.28 (m, 4H), 2.22 (m, 4H), 2.19 (s, 3H), 2.13 (s, 3H), 1.48(s, 3H)

[1411] MS m/z 473 [M−1].

Example 2142-]4-(2-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1412]

[1413]¹H NMR (400 MHz, DMSO-d₆) 813.80 (s, 1H, NH), 11.18 (br s, 1H,NH), 1H), 7.62 (s, 1H), 7.47 (m, 1H), 7.37 (m, 2H), 7.30 (m, 1H) , 7.18(t, 1H), 6.92 (dd, 1H), 6.67 (dd, 1H), 6.32 (d, 1H), 3.1 (m, 2H), 2.42(m, 6H), 2.27 (s, 3H), 1.67 (m, 4H).

[1414] MS m/z 473 [M−1].

Example 2152-]4-(2-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1415]

[1416]¹H NMR (400 MHz, DMSO-d₆) 67 13.81 (s, 1H, NH), 7.82 (t, l H),7.59 (s, 1H), 7.46 (m, 1H), 7.37 (m, 2H), 7.29 (m, 1H), 7.17 (t, 1H),6.91 (dd, 1H), 6.66 (dd, 1H), 6.29 (t, 1H), 3.05 (m, 2H), 2.40 (m, 6H),2.22 (s, 3H), 1.7 (m, 4H), 1.49 (m 2H).

[1417] MS m/z 488 [M−1].

Example 2164-(2-Chloro-phenyl)-3-[1-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1418]

[1419]¹H NMR (400 MHz, DMSO-d₆) 613.45 (s, 1H, NH), 11.12 (s, 1H, NH),7.66 (m, 2H), 7.52 (m, 2H), 7.43 (m, 1H), 7.35 (d J=3.1 Hz, 1H), 7.21(t, J=7.8 Hz, 2H), 6.93 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.76 (dd, J=0.8Hz, J=7.4 Hz, 1H), 6.45 (s, 1H), 3.42 (m, 4H), 2.22 (m, 4H), 2.18 (s,3H), 1.60 (s, 3H)

[1420] MS m/z 459[M−1].

Example 2174-(3-Methoxy-phenyl)-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1421]

[1422]¹H NMR (400 MHz, DMSO-d₆) 813.49 (s, 1H, NH), 11.08 (s, 1H, NH),7.44 (t, J=8.2 Hz, 1H), 7.38 (d, J=3.1 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H),7.09 (m , 1H), 6.95 (m, 2H), 6.89 (s, 1H), 6.87 (d, J=0.8 Hz, 1H), 6.78(dd, J=0.8 Hz, J=7.4 Hz, 1H), 3.75 (s, 3H), 3.51 (m, 4H), 3.43 (m, 4H),1.63 (s, 3H).

[1423] MS m/z 442 [M−1].

Example 2184-(3-Chloro4-fluoro-phenyl)-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1424]

[1425]¹H NMR (400 MHz, DMSO-d₆) δ 13.41 (s, 1H, NH), 11.13 (s, 1H, NH),7.70 (dd, J=2.2 Hz, J=7.4 Hz, 1H), 7.59 (t, J=9.0 Hz, 1H), 7.46 (m, 1H),7.40 (d, J=3.1 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H),6.92 (dd, J=0.8 Hz, J=7.4 Hz, 1H), 6.80 (dd, J=0.8 Hz, J=7.4 Hz, 1H),6.76 (s, 1H), 3.52 (m, 4H), 3.38 (m, 4H), 1.69 (s, 3H).

[1426] MS m/z 464 [M−1].

Example 2193-[1-{3,5-Dimethyl-4-[2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(3fluoro-phenyl)-1,3-dihydro-indol-2-one

[1427]

[1428]¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (s, 1H, NH), 10.93 (s, 1H, NH),7.56 (m, 1H), 7.28 (m, 3H), 7.13 (t, 1H), 6.90 (dd, 1H), 6.75 (dd, 1H),6.74 (s, 1H), 4.13 (m, 1H), 3.58 (m, 1H), 3.39 (s, 2H), 3.05 (m, 1H),2.71 (m, 1H), 2.47 (m, 4H), 2.19 (m, 5H), 1.79 (m, 2H), 1.65 (m, 4H),1.52 (s, 3H), 1.2 (m, 1H).

[1429] MS m/z 525 [M−1].

Example 2202-{5-]4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-N-(2-hydroxy-3-[1,2,3]triazol-2-yl-propyl)-acetamide

[1430]

[1431]¹H NMR (400 MHz, DMSO-d₆) 67 13.30 (s, 1H, NH), 10.93 (s, 1H, NH),7.87 (t, 1H), 7.74 (s, 2H), 7.55 (m, H), 7.26 (m, 3H), 7.13 (t, 1H),6.90 (d, H), 6.75 (m, H), 5.22 (m, 1H), 4.29 (m, 2H), 4.02 (m, 1H), 3.17(s, 2H), 3.06 (m, 2H), 2.23 (s, 3H), 1.56 (s, 3H).

[1432] MS m/z 513 [M−1].

Example 2213-l1-[3,5-Dimethyl-4-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1433]

[1434]¹H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H, NH), 10.92 (s, 1H, NH),7.56 (m, 1H), 7.28 (m, 3H), 7.13 (t, J=7.8 Hz, 1H), 6.90 (dd, J=0.8 Hz,J=7.8 Hz, 1H), 6.75 (dd, J=1.0 Hz, J=7.4 Hz, 1H), 6.75 (s, 1H), 3.49 (m,6H), 3.39 (m, 4H), 2.19 (s, 3H), 1.51 (s, 3H).

[1435] MS m/z 458 [M−1].

Example 2224-(3-Fluoro-phenyl)-3-[1-{4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1436]

[1437]¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, 1H, NH), 10.92 (s, 1H, NH),7.56 (m, 1H), 7.28 (m, 3H), 7.13 (t, J=7.8 Hz, 1H), 6.90 (d, J=7.4 Hz,1H), 6.75 (dd, J=0.78 Hz, J=7.8 Hz, 1H), 6.74 (s, 1H), 4.72 (d, J=3.9Hz, 1H), 3.89 (m, 1H), 3.68 (m, 2H), 3.39 (m, 2H), 3.15 (m, 1H), 2.95(m, 1H), 2.19 (s, 3H), 1.67 (m, 2H), 1.52 (s, 3H), 1.19 (m, 2H).

[1438] MS m/z 472 [M−1].

Example 2232-{5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-N-(2-morpholin-4-yl-ethyl)-acetamide

[1439]

[1440]¹H NMR (400 MHz, DMSO-d₆) δ 13.31 (s, 1H, NH), 10.94 (s, 1H, NH),7.56 (m, 2H), 7.28 (m, 3H), 7.13 (t, J=7.6 Hz, 1H), 6.90 (dd, J=0.8 Hz,J=7.8 Hz, 1H), 6.76 (d, J=0.8 Hz, 1H), 6.74 (s, 1H), 3.54 (m, 2H), 3.50(m, H), 3.15 (s, 2H), 3.19 (m, 2H), 2.29 (m, 6H), 2.25 (s, 3H), 1.60 (s,3H).

[1441] MS m/z 501 [M−1].

Example 224N-(2-Diethylamino-ethyl)-2-{5-]4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetamide

[1442]

[1443]¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (s, 1H, NH), 10.93 (s, 1H, NH),7.56 (m, H), 7.41 (t, J=5.6 Hz, 1H), 7.28 (m, 3H), 7.13 (t,=7.8 Hz, 1H),6.90 (d, J=7.0 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 6.74 (s, 1H), 3.14 (s,2H), 3.04 (m, 2H), 2.38 (m, 6H), 2.24 (s, 3H), 1.57 (s, 3H), 0.88 (t,J=7.2 Hz, 6H).

[1444] MS m/z 487 [M−1].

Example 2252-{5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-acetamide

[1445]

[1446]¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, 1H, NH), 10.92 (s, 1H, NH),7.64 (t, 1H), 7.56 (m, 1H), 7.27 (m, 3H), 7.13 (t, J=7.8 Hz, 1H), 6.90(dd, J=0.78 Hz, J=7.8 Hz, 1H), 6.75 (dd, J=0.78 Hz, J=7.8 Hz, 1H), 6.74(s, 1H), 3.14 (s, 2H), 3.11 (m, 2H), 2.42 (m, 6H), 2.24 (s, 3H), 1.65(m, 4H), 1.57 (s, 3H).

[1447] MS m/z 485 [M−1].

Example 2263-[1-{4-[2-((cis)-3,5-Dimethyl-piperazin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1448]

[1449]¹H NMR (400 MHz, DMSO-d₆) 813.29 (s, 1H, NH), 10.92 (s, 1H, NH),7.56 (m, 1H), 7.27 (m, 3H), 7.14 (t, J=7.6 Hz, 1H), 6.92 (dd, J=0.77 Hz,J=7.8 Hz, 1H), 6.75 (dd, J=0.78 Hz, J=7.8 Hz, 1H), 6.74 (s, 1H), 4.19(m, 1H), 3.75 (m, 1H), 3.45 (d, J=16.8 Hz, 1H), 3.13 (d, J=16.8 Hz, 1H),2.45 (m, 3H), 2.20 (m, 1H), 2.19 (s, 3H), 1.99 (m, 1H), 1.52 (s, 3H),0.91 (m, 6H).

[1450] MS m/z 485 [M−1].

Example 2272-{5-]4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-N-(2-pyridin-4-yl-ethyl)-acetamide

[1451]

[1452]¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, 1H, NH), 10.92 (s, 1H, NH),8.41 (dd, 2H), 7.74 (t, 1H), 7.57 (m, 1H), 7.29 (m, 3H), 7.13 (m, 3H),6.90 (d, 1H), 6.76 (d, 1H), 6.73 (s, 1H), 3.28 (m, 2H), 3.11 (s, 2H),2.69 (t, 2H), 2.19 (s, 3H), 1.51 (s, 3H).

[1453] MS m/z 493 [M−1].

Example 2282-Fluoro-5-{3-1[-[5-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-benzonitrile

[1454]

[1455]¹H NMR (400 MHz, DMSO-d₆) δ 13.59 (s, NH, 1H), 11.17 (s, NH, 1H),7.93 (dd, J=2.3 Hz, J=6.3 Hz, 1H), 7.73 (m, 1H), 7.63 (m, 1H), 7.21 (t,J=7.6 Hz, 1H), 6.94 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.87 (m, 1H), 6.78 (d,J=6.6 Hz, 1H), 6.11 (d, J=1.9 Hz, 1H), 4.25 (m, 1H), 3.85 (m, 1H), 2.95(m, 8H), 1.90 (m, 6H), 1.42 (m, 1H).

[1456] MS m/z 522 [M−1].

Example 2292-[4-(3-Cyano4-fluoro-phenyl)-2-oxo-1,2-dibydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-[1,2,3]triazol-2-yl-propyl)-amide

[1457]

[1458]¹H NMR (400 MHz, DMSO-d6) δ 13.79 (s, NH, 1H), 11.17 (s, NH, 1H),8.00 (t, 1H), 7.93 (s, 1H), 7.91 (dd, 1H), 7.75 (s, 2H), 7.68 (m, 1H),7.50 (t, 1H), 7.21 (t, 1H), 6.94 (d, 1H), 6.78 (d, 1H), 6.51 (d, 1H),5.14 (d, 1H), 4.32 (m, 2H), 4.09 (m, 1H), 3.12 (m, 2H), 2.30 (s, 3H).

[1459] MS m/z 510 [M−1].

Example 2305-{3-[1-[3-((cis)-3,5-Dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-2-fluoro-benzonitrile

[1460]

[1461]¹H NMR (400 MHz, DMSO-d₆) δ 13.59 (s, NH, 1H), 11.15 (s, NH, 1H),7.93 (dd, J=2.3 Hz, J=6.3 Hz, 1H), 7.72 (m, 1H), 7.54 (m, 1H), 7.20 (t,J=7.6 Hz, 1H), 6.94 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.87 (s, 1H), 6.76(dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.08 (d, J=2.0 Hz, 1H), 4.18 (m, 1H), 3.57(m, 1H), 2.42 (m, 2H), 2.31 (s, 3H), 2.26 (m, 1H), 2.07 (m, 1H), 1.02(m, 3H), 0.96 (m, 1H), 0.82 (m, 3H).

[1462] MS m/z 482 [M−1].

Example 2313-[1-[3-(3-Dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1463]

[1464]¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (s, 1H, NH), 10.91 (s, 1H, NH),7.45 (m, 2H), 7.34 (m, 2H), 7.11 (t, J=7.6 Hz, 1H), 6.88 (dd, J=0.78 Hz,J=7.8 Hz, 1H), 6.82 (s, 1H), 6.71 (d, J=7.8 Hz, 1H), 2.62 (m, 2H), 2.33(m, 2H), 2.07 (s, 6H), 1.97 (m, 4H), 1.69 (m, 4H), 1.20 (m, 2H).

[1465] MS m/z 444 [M⁺+1].

Example 2323-1-[3-(3-Dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1466]

[1467]¹H NMR (400MHz, DMSO-d₆) δ 13.25 (s, 1H, NH), 10.93 (s, 1H, NH),7.57 (m, H), 7.44 (m, 1H), 7.37 (m, 2H), 7.14 (t, J=7.8 Hz, 1H), 6.92(d, J=7.8 Hz, 1H), 6.75 (d, J 7.4 Hz, 1H), 6.7 (s, 1H), 2.62 (t, J=5.9Hz, 2H), 2.32 (m, 2H), 2.06 (s, 6H), 1.91 (m, 4H), 1.68 (m, 4H), 1.18(m, 2H).

[1468] MS m/z 444 [M⁺+1].

Example 2334-(4-Chloro-phenyl)-3-[1-[3-(3-dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indol-2-y-meth-(Z)-ylidene-1,3-dihydro-indol-2-one

[1469]

[1470]¹H NMR (400 MHz, DMSO-d₆) δ ¹3.25 (s, 1H, NH), 10.92 (s, 1H, NH),7.56 (m, 2H), 7.45 (m, 2H), 7.12 (t, J=7.6 Hz, 1H), 6.89 (dd, J=0.78 Hz,J=7.8 Hz, 1H), 6.85 (s, 1H), 6.71 (dd, J=0.78 Hz, J=7.8 Hz, 1H), 2.62(m, 2H), 2.32 (m, 2H), 2.07 (s, 6H), 1.97 (m, 4H), 1.68 (m, 4H), 1.18(m, 2H).

[1471] MS m/z 459 [M−1].

Example 234 4-(3-Chloro-phenyl)-3-[1-[3-(3-dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1472]

[1473]¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (s, 1H, NH), 10.93 (s, 1H, NH),7.54 (m, H), 7.48 (m, 1H), 7.39 (m, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.90(d, J=6.6 Hz, 1H), 6.83 (s, 1H), 6.73 (dd, J=0.78 Hz, J=7.8 Hz, 1H),2.62 (m, 2H), 2.33 (m, 2H), 2.05 (s, 6H), 1.94 (m, 4H), 1.68 (m, 4H),1.18 (m, 2H).

[1474] MS m/z 460 [M⁺+1].

Example 2354-(2-Chloro-phenyl)-3-[1-[3-(3-dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1475]

[1476]¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (s, 1H, NH), 10.93 (s, 1H, NH),7.63 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 7.53 (m, 2H), 7.42 (m, 1H), 7.14 (t,J=7.6 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.68 (d, J=7.8 Hz, 1H), 6.49 (s,1H), 2.61 (m, 2H), 2.31 (m, 2H), 2.11 (s, 6H), 2.01 (m, 2H), 1.85 (m,2H), 1.68 (m, 4H), 1.21 (m, 2H).

[1477] MS m/z 460 [M⁺+1].

Example 2364-Biphenyl-3-yl-3-[1-f3,5-dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1478]

[1479] MS m/z 569 [M−1].

Example 2375-[4-Biphenyl-3-yl-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)-amide

[1480]

[1481]¹H NMR (400 MHz, DMSO-d6) δ 13.49 (s, 1H, NH), 11.06 (s, 1H, NH),8.03 (d, J=0.78 Hz, 1H), 7.67 (m, 6H), 7.39 (m, 5H), 7.20 (t, J=7.6 Hz,1H), 6.93 (dd, J=0.78 Hz, J=7.8 Hz, 1H), 6.87 (s, 1H), 6.85 (s, 1H),5.32 (m, 1H), 4.22 (m, 1H), 3.20 (m, 4H), 2.36 (s, 3H), 1.61 (s, 3H).

[1482] MS m/z 557 [M−1].

Example 238 4-Biphenyl-3-yl-3-[1-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1483]

[1484] MS m/z 529 [M−1].

Example 2394-(3-Fluoro-phenyl)-3-[1-[4-(4-hydroxy-piperidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1485]

[1486]¹H NMR (400 MHz, DMSO-d₆) δ 13.41 (s, 1H, NH), 11.05 (s, 1H, NH),7.57 (m, 1H), 7.28 (m, 3H), 7.17 (t, J=7.6 Hz, 1H), 6.92 (dd, J=0.78 Hz,J=7.8 Hz, 1H), 6.78 (dd, J=0.78 Hz, J=7.8 Hz, 1H), 6.75 (s, 1H), 4.7 (d,J=4.3 Hz, 1H), 3.95 (br m, 1H), 3.67 (m, 1H), 3.45 (br m, 1H), 3.07 (m,2H), 2.23 (s, 3H), 1.69 (m, 2H), 1.58 (s, 3H), 1.24 (m, 2H).

[1487] MS m/z 458 [M−1].

Example 2403-[1-[3,5-Dimethyl-4-(4-pyridin-2-yl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1488]

[1489]¹H NMR (400 MHz, DMSO-d₆) δ 13.47 (s, 1H, NH), 11.07 (s, 1H, NH),8.10 (dd, J=1.7 Hz, J=4.7 Hz, 1H), 7.54 (m, 2H), 7.29 (m, 3H), 7.18 (t,J=7.6 Hz, 1H), 6.93 (dd, J=0.78 Hz, J=7.8 Hz, 1H), 6.79 (m, 3H), 6.64(m, 1H), 3.47 (m, 4H), 3.49 (m, 4H), 2.26 (s, 3H), 1.62 (s, 3H).

[1490] MS m/z 520 [M−1].

Example 2415-[4-(3-Fluoro-phenyl)-2-oxo1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole3-carboxylicacid (2-piperidin-1 -yl-ethyl)-amide

[1491]

[1492]¹H NMR (400 MHz, DMSO-d₆) δ 13.45 (s, 1H, NH), 11.05 (s, 1H, NH),7.58 (m, 1H), 7.30 (m, 4H), 7.17 (t, J=7.8 Hz, 1H), 6.92 (dd, J=1.2 Hz,J=7.8 Hz, 1H), 6.79 (dd, J=0.78 Hz, J=7.8 Hz, 1H), 6.77 (s, 1H), 3.27(m, 2H), 2.39 (s, 3H), 2.36 (m, 6H), 1.73 (s, 3H), 1.47 (m, 4H), 1.38(m, 2H).

[1493] MS m/z 485 [M−1].

Example 2425-[4-Biphenyl-2-yl-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide

[1494]

[1495]¹H NMR (400 MHz, DMSO-d₆) 613.45 (s, 1H, NH), 11.05 (s, 1H, NH),7.53 (m, 3H), 7.35 (m, 2H), 7.07 (m, 6H); 7.77 (d, J=7.0 Hz, 1H), 6.73(d, J=7.4 Hz, 1H), 6.56 (s, 1H), 3.34 (s, 2H), 2.48 (m, 6H), 2.36 (s,3H), 1.73 (s, 3H), 0.95 (t, 6H).

[1496] MS m/z 531 [M−1].

Example 2432-[4-Biphenyl-2-yl-2-oxo1,2dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1497]

[1498]¹H NMR (400 MHz, DMSO-d₆) δ 13.7 1 (s, 1H, NH), 10.91 (s, 1H, NH),7.84 (t, 1H), 7.64 (s, 1H), 7.41 (m, 3H), 7.24 (d, 1H), 7.07d(m, H),6.76 (dd 1H), 6.38 (dd 1H), 6.28 (d, 1H), 3.19 (m, 2H), 2.50 (m, 4H),2.41 (m, 2H), 2.28 (s, 3H), 1.65 (m, 6H).

[1499] MS m/z 529 [M−1].

Example 2442-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1 -yl-propyl)-amide

[1500]

[1501]¹H NMR (400 MHz, DMSO-d₆) δ 13.81 (s, NH, 1H), 11.12 (br s, NH,1H), 7.99 (s, 1H), 7.88 (m, 1H), 7.44 (m, 2H), 7.35 (m, 2H), 7.19 (t,J=7.8 Hz, 1H), 6.92 (d, J=7.4 Hz, 1H), 6.75 (d, J=7.4 Hz, 1H), 6.36 (s,1H), 3.12 (m, 2H), 2.42 (m, 6H), 2.30 (s, 3H), 1.67 (m, 4H), 1.60 (m,2H).

[1502] MS m/z 487 [M−1].

Example 2452-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1503]

[1504]¹H NMR (400 MHz, DMSO-d₆) δ 13.81 (s, NH, 1H), 11.16 (br s, NH,1H), 7.99 (s, 1H), 7.88 (m, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.39 (m, 2H),7.32 (d, J=7.0 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H),6.76 (d, J=7.8 Hz, 1H), 6.35 (s, 1H), 3.12 (m, 2H), 2.42 (m, 6H), 2.30(s, 3H), 1.69 (m, 4H), 1.60 (m, 2H).

[1505] MS m/z 487 [M−1].

Example 2462-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1506]

[1507]¹H NMR (400 MHz, DMSO-d₆) δ 13.81 (s, NH, 1H), 11.14 (br s, NH,1H), 7.98 (s, 1H), 7.88 (m, 1H), 7.44 (m, 1H), 7.18 (m, 4H), 6.92 (d,J=7.0 Hz,1H), 6.77 (d, J=7.0 Hz, 1H), 6.34 (s, 1H), 3.07 (m, 2H), 2.42(m, 6H), 2.30 (s, 3H), 1.69 (m, 4H), 1.59 (m, 2H).

[1508] MS m/z 471 [M−1].

Example 2472-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1 -yl-propyl)-amide

[1509]

[1510]¹H NMR (400 MHz, DMSO-d₆) δ 13.81 (s, NH, 1H), 11.16 (br s, NH,1H), 8.01 (s, 1H), 7.87 (m, 1H), 7.57 (m, 2H), 7.29 (m, 2H), 7.19 (t,J=7.8 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.75 (dd, J=1.2 Hz, J=7.8 Hz,1H), 6.36 (m, 1H), 3.15 (m, 2H), 2.42 (m, 6H), 2.30 (s, 3H), 1.67 (m,4H), 1.61 (m, 2H).

[1511] MS m/z 531,533 [M−1].

Example 2485-Methyl-2-[2-oxo4-phenyl-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1512]

[1513]¹H NMR (400 MHz, DMSO-d₆) δ 13.80 (s, NH, 1H), 11.16 (s, NH, 1H),7.89 (s, 1H), 7.82 (m, 1H), 7.37 (m, 5H), 7.17 (t, J=7.8 Hz, 1H), 6.90(d, J=7.0 Hz, 1H), 6.75 (d, J=7.0 Hz, 1H), 6.29 (m, 1H), 3.03 (m, 2H),2.42 (m, 6H), 2.29 (s, 3H), 1.68 (m, 4H), 1.56 (m, 2H).

[1514] MS m/z 453 [M−1].

Example 2495-[4-(3,5-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1515]

[1516]¹H NMR (400 MHz, DMSO-d₆) δ 13.45 (s, NH, 1H), 11.08 (s, NH, 1H),7.48 (m, 1H), 7.40 (m, 1H), 7.22 (m, 2H), 7.18 (t, J=7.8 Hz, 1H), 6.92(dd, J=0.8 Hz, J=7.4 Hz, 1H), 6.80 (m, 2H), 3.26 (m, 2H), 2.51 (m, 2H),2.44 (m, 4H), 2.36 (s, 3H), 1.78 (s, 3H), 1.64 (m, 4H).

[1517] MS m/z 489 [M−1].

Example 2502-[4-(3,5-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1 -yl-propyl)-amide

[1518]

[1519]¹H NMR (400 MHz, DMSO-d₆) δ 13.77 (s, NH, 1H), 11.13 (s, NH, 1H),8.05 (s, 1H), 7.94 (m, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.11 (m, 1H), 7.05(m, 2H), 6.93 (d, J=7.8 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 6.38 (m, 1H),3.10 (m, 2H), 2.42 (m, 6H), 2.30 (s, 3H), 1.68 (m, 4H), 1.59 (m, 2H).

[1520] MS m/z 489 [M−1].

Example 2514-(3,5-Difluoro-phenyl)-3-[1-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1521]

[1522]¹H NMR (400 MHz, DMSO-d₆) δ 13.43 (s, NH,1H), 11.08 (s, NH, 1H),7.39 (m, 1H), 7.20 (m, 3H), 6.94 (d, J=7.4 Hz, 1H), 6.80 (m, 2H), 3.42(m, 4H), 2.26 (m, 4H), 2.22 (s, 3H), 2.15 (s, 3H), 1.65 (s, 3H).

[1523] MS m/z 475 [M−1].

Example 2524-(3,5-Difluoro-phenyl)-3-[1-[5-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1524]

[1525]¹H NMR (400 MHz, DMSO-d₆) δ 13.54 (s, NH, 1H), 11.12 (s, NH, 1H),7.24 (m, 1H), 7.18 (m, 1H), 7.06 (m, 2H), 6.93 (m, 2H), 6.76 (d, J=7.0Hz, 1H), 6.09 (s, 1H), 4.11 (m, 1H), 3.59 (m, 1H), 2.84 (m, 2H), 2.45(m, 4H), 2.31 (s, 3H), 2.17 (m, 1H), 1.58 (m, 1H), 1.65 (m, 5H), 1.21(m, 2H).

[1526] MS m/z 515 [M−1].

Example 2533-[1-{3,5-Dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro-indol-2-one

[1527]

[1528]¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (s, NH, 1H), 10.85 (s, NH, 1H),7.41 (t, J=7.4 Hz, 1H), 7.31 (d, J=7.4 Hz, 1H), 7.23 (s, 1H), 7.18 (d,J=7.8 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.71 (m,2H), 4.64 (m, 1H), 3.60 (m, 2H), 3.37 (m, 2H), 3.24 (m, 2H), 2.76 (t,J=7.4 Hz, 2H), 2.35 (m, 4H), 2.21 (s, 3H), 2.13 (m, 4H), 2.07 (s, 3H),1.49 (s, 3H).

[1529] MS m/z 511 [M−1].

Example 2543-[1-{4-[³-((cis)-3,5-Dimethyl-piperazin-1-yl)-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro-indol-2-one

[1530]

[1531] MS m/z 525 [M−1].

Example 255 4-[3-(2-Hydroxy-ethyl)-phenyl]-3-[1-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1532]

[1533]¹H NMR (400 MHz, DMSO-d₆) δ 13.48 (s, NH,1H), 11.08 (s, NH, 1H),7.44 (t, J=7.4 Hz, 1H), 7.35 (d, J=3.1 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H),7.26 (s, 1H), 7.22 (m, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.90 (d, J=7.8 Hz,1H), 6.78 (m, 2H), 4.64 (t, J=5.1 Hz, 1H), 3.60 (m, 2H), 3.43 (m, 4H),2.77 (t, J=7.0 Hz, 2H), 2.24 (m, 4H), 2.15 (s, 3H), 1.57 (s, 3H).

[1534] MS m/z 469 [M−1].

Example 256 3-[1-[4-((cis)-3,5-Dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro-indol-2-one

[1535]

[1536]¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, NH, 1H), 11.08 (s, NH, 1H),7.44 (t, J=7.8 Hz, 1H), 7.34 (m, 2H), 7.26 (s, 1H), 7.21 (d, J=7.4 Hz,1H), 7.18 (t, J=7.8 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.77 (m, 2H), 4.63(t, J=5.1 Hz, 1H), 4.10 (m, 1H), 3.60 (m, 2H), 2.77 (t, J=7.0 Hz, 2H),2.56 (m, 4H), 2.30 (m, 2H), 1.56 (s, 3H), 0.90 (m, 6H).

[1537] MS m/z 483 [M−1].

Example 2572-[4-[3-(2-Hydroxy-ethyl)-phenyl]-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1 -yl-propyl)-amide

[1538]

[1539]¹H NMR (400 MHz, DMSO-d₆) δ 13.79 (s, NH, 1H), 11.08 (s, NH, 1H),7.95 (m, 1H), 7.86 (s, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.16 (m, 3H), 7.11(d, J=7.8 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.73 (dd, J=1.2 Hz, J=7.8 Hz,1H), 6.32 (m, 1H), 4.55 (br m, 1H), 3.61 (m, 2H), 3.02 (m, 2H), 2.72 (t,J=6.6 Hz, 2H), 2.43 (m, 6H), 2.28 (s, 3H), 1.67 (m, 4H), 1.57 (m, 2H).

[1540] MS m/z 497 [M−1].

Example 258 3-[l1-[3-((cis)-3,5-Dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro-indol-2-one

[1541]

[1542]¹H NMR (400 MHz, DMSO-d₆) δ 13.65 (s, NH, 1H), 11.20 (s, NH, 1H),7.30 (br m, 1H), 7.20 (m, 1H), 7.18 (m, 3H), 6.96 (br m, 1H), 6.88 (dd,J=0.8 Hz, J=7.8 Hz, 1H), 6.71 (dd, J=0.8 Hz, J=7.4 Hz, 1H), 6.02 (d,J=2.3 Hz, 1H), 4.61 (m, 1H), 4.06 (m, 1H), 3.63 (m, 2H), 2.75 (m, 2H),2.46 (m, 4H), 2.29 (s, 3H), 2.0 (m, 2H), 1.03 (m, 3H), 0.77 (m, 3H).

[1543] MS m/z 483 [M−1].

Example 259(3-{3-[1-[3-Methyl-4-(morpholine4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol4-yl}-phenyl)-aceticacid

[1544]

[1545] [3-(2-Oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetic acid (80.1mg, 0.3 mmol) was condensed with3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (66.7 mg,0.3 mmol) in ethanol to give 75.3 mg of the titled compound.

[1546]¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, NH, 1H), 12.29 (s, 1H),11.09 (s, NH, 1H), 7.48 (t, J=7.4 Hz, 1H), 7.37 (m, 2H), 7.30 (s, 1H),7.27 (d, J=7.4 Hz, 1H), 7.19 (t, J=7.4 Hz, 1H), 6.90 (dd, J=0.8 Hz,J=7.8 Hz, 1H), 6.76 (m, 2H), 3.64 (s, 2H), 3.52 (m, 4H), 3.44 (m, 4H),1.58 (s, 3H).

[1547] MS m/z 472 [M⁺+1].

Example 2604-{3-[2-((cis)-3,5-Dimethyl-piperazin-1-yl)-2-oxo-ethyl]-phenyl}-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1548]

[1549] (3-(3-{3-[1-[3-Methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-phenyl)-aceticacid was coupled with (2S, 6R)-2,6-dimethyl-piperazine (3 eq.), EDC (1.5eq.) and HOBt (1 eq.) in THF using the general amidation procedure togive the titled compound.

[1550]¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, NH, 1H), 11.09 (s, NH, 1H),7.46 (t, J=7.8 Hz, 1H), 7.38 (d, J=3.1 Hz, 1H), 7.34 (br m, 1H), 7.27(m, 2H), 7.19 (t, J=7.8 Hz, 1H), 6.90 (d, J=7.4 Hz, 1H), 6.79 (s, 1H),6.75 (d, J=7.8 Hz, 1H), 4.21 (m, 1H), 3.82 (m, 1H), 3.76 (s, 2H), 3.51(m, 4H), 3.44 (m, 4H), 2.42 (m, 4H), 1.97 (m, 1H), 1.60 (s, 3H), 0.90(d, 3H), 0.81 (d, 3H).

[1551] MS m/z 566 [M−1].

Example 261N-(2-Dimethylamino-ethyl)-2-(3-{3-[1-[3-methyl4-(morpholine4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol4-yl}-phenyl)-acetamide

[1552]

[1553] (3-{3-[1-[3-Methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-phenyl)-aceticacid (117.6 mg, 0.25 mmol) was coupled with N,N-dimethylethylenediamine(2 eq.), EDC (1.5 eq.) and HOBt (1 eq.) in DMF (1 mL) using the generalamidation procedure to give 117.3 mg of the titled compound.

[1554]¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, NH, 1H), 11.09 (s, NH, 1H),7.98 (m, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.36 (m, 3H), 7.24 (d, J=7.4 Hz,1H), 7.19 (t, J=7.6 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.76 (m, 2H), 3.52(m, 4H), 3.44 (m, 4H), 3.31 (s, 2H), 3.05 (m, 2H), 2.16 (t, J=7.0 Hz,2H), 2.03 (s, 6H), 1.57 (s, 3H).

[1555] MS m/z 540 [M−1].

Example 2625-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-phenyl-1H-pyrrole-3-carboxylicacid methyl-(1-methyl-piperidin-4-yl)-amide

[1556]

[1557] MS m/z 533 [M−1].

Example 2635-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-phenyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide

[1558]

[1559]¹H NMR (400 MHz, DMSO-d₆) δ 13.99 (s, NH, 1H), 11.21 (s, NH, 1H),7.69 (d, J=2.9 Hz, 1H), 7.32 (m, 1H), 7.21 (m, 4H), 7.04 (m, 1H), 6.98(m, 1H), 6.92 (m, 4H), 6.79 (m, 1H), 6.69 (s, 1H), 6.68 (d, J=7.8 Hz,1H), 3.05 (m, 2H), 2.30 (m, 6H), 0.82 (t, J=7.0 Hz, 6H).

[1560] MS m/z 521 [M−1].

Example 2645-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-phenyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1561]

¹H NMR (400 MHz, DMSO-d₆) δ 13.99 (s, NH, 1H), 11.21 (s, NH, 1H), 7.70(d, J=3.4 Hz, 1H), 7.32 (t, J=7.3 Hz, 1H), 7.23 (t, J=7.4 Hz, 1H), 7.18(m, 3H), 7.04 (m, 1H), 6.97 (m, 1H), 6.90 (m, 3H1), 6.83 (m, 1H), 6.78(m, 1H), 6.67 (m, 2H), 3.10 (m, 2H), 2.27 (m, 6H), 1.57 (m, 4H).

[1562] MS m/z 5l9 [M−1].

Example 265 N,N-Dimethyl-2-(3-{3-1 I-[3-methyl-4-(4-methyl-piperazine-1-

[1563]carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-phenyl)-acetamide

[1564]¹H NMR (400 MHz, DMSO-d₆) δ 13.47 (s, NH,1H), 11.08 (s, NH, 1H),7.46 (m, 1H), 7.35 (m, 21), 7.26 (m, 2H), 7.19 (t, J=7.8 Hz, 11H), 6.90(dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.77 (m, 2H), 3.73 (s, 2H), 3.42 (m, 4H),2.96 (s, 3H), 2.76 (s, 3H), 2.23 (m, 4H), 2.15 (s, 3H), 1.57 (s, 3H).

[1565] MS m/z 510 [M−1].

Example 2662-(3-{3-[1-[3,5-Dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-phenyl)-N,N-dimethyl-acetamide

[1566]

[1567]¹H NMR (400 MHz, DMSO-d₆) δ 13.40 (s, NH, 1H), 11.01 (s, NH, 1H),7.46 (m, 1H), 7.31 (m, 1H), 7.25 (m, 2H), 7.16 (t, J=7.4 Hz, 1H), 6.90(d, J=7.8 Hz, 1H), 6.75 (d, J=7.4 Hz, 1H), 6.69 (s, 1H), 4.08 (m, 1H),3.73 (s, 2H), 3.40 (m, 1H), 2.95 (s, 3H), 2.90 (m, 2H), 2.76 (s, 3H),2.43 (m, 4H), 2.20 (s, 3H), 2.16 (m, 1H), 1.74 (m, 2H), 1.63 (m, 4H),1.50 (s, 3H), 1.15 (m, 1H).

[1568] MS m/z 578 [M−1].

Example 2675-[4-(3-Dimethylcarbamoylmethyl-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide

[1569]

[1570]¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, NH, 1H), 11.03 (s, NH, 1H),7.45 (m, 1H), 7.34 (m, 2H), 7.25 (m, 2H), 7.16 (t, J=7.8 Hz, 1H), 6.90(dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.75 (m, 2H), 3.73 (s, 2H), 3.23 (m, 2H),2.95 (s, 3H), 2.77 (s, 3H), 2.52 (m, 6H), 2.36 (s, 3H), 1.64 (s, 3H),0.95 (m, 6H) or (t, J=7.0 Hz, 6H)

[1571] MS m/z 540 [M−1].

Example 2683-[1-[3,5-Dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro-indol-2-one

[1572]

[1573]¹H NMR (400 MHz, DMSO-d₆) δ 13.40 (s, NH, 1H), 10.99 (s, NH, 1H),7.43 (m, 1H), 7.31 (m, 1H), 7.24 (s, 11H), 7.20 (d, J=7.4 Hz, 1H), 7.15(t, J=7.4 Hz, 1H), 6.89 (dd, J=0.8 Hz, J=7.4 Hz, 1H), 6.75 (dd, J=0.8Hz, J=7.4 Hz, 1H), 6.71 (s, 1H), 4.63 (t, J=5.1 Hz, 1H), 4.17 (m, 1H),3.59 (m, 3H), 2.92 (m, 2H), 2.76 (t, J=7.4 Hz, 2H), 2.43 (s, 3H), 2.20(m, 5H), 1.78 (m, 2H), 1.64 (m, 5H), 1.49 (s, 3H), 1.22 (m, 1H).

[1574] MS m/z 537 [M−1].

Example 2694-[3-(2-Dimethylamino-ethyl)-phenyl]-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1575]

[1576]¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, NH, 1H), 11.09 (s, NH, 1H),7.44 (m, 1H), 7.38 (d, J=3.1 Hz, 1H), 7.33 (m, 1H), 7.26 (m, 1H), 7.19(m, 2H), 6.89 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 6.77 (m, 2H), 3.51 (m, 4H),3.44 (m, 4H), 2.76 (t, J=7.4 Hz, 2H), 2.45 (m, 2H), 2.14 (s, 6H), 1.59(s, 3H).

[1577] MS m/z 483 [M-l].

Example 2704-[3-(2-Dimethylamino-ethyl)-phenyl]-3-[1-[4-(4-hydroxy-piperidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1578]

[1579]¹H NMR (400 MHz, DMSO-d₆) δ 13.41 (s, NH, 1H), 11.01 (br s, NH,1H), 7.41 (m, 1H), 7.32 (m, 1H), 7.24 (s, 1H), 7.20 (m, 1H), 7.15 (t,J=7.8 Hz, 1H), 6.89 (dd, J=1.2 Hz, J=6.6 Hz, 1H), 6.75 (dd, J=0.8 Hz,J=7.8 Hz, 1H), 6.69 (s, 1H), 4.73 (m, 1H), 3.65 (m, 1H), 3.11 (m, 4H),2.74 (t, J=7.4 Hz, 2H), 2.43 (m, 2H), 2.20 (s, 3H), 2.11 (s, 6H), 1.69(m, 3H), 1.50 (s, 3H), 1.22 (m, 1H).

[1580] MS m/z 511 [M−1].

Example 271 3-{3-[l-[3-Methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide

[1581]

[1582]¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, 1H, NH), 11.13 (s, 1H, NH),8.53 (t, 1H), 7.93-7.97 (m, 2H), 7.64 (t, 1H), 7.58 (d, 1H), 7.39 (d,1H), 7.22 (t, 1H), 6.93 (d, 1H), 6.82 (d, 1H), 6.80 (s, 1H), 3.51 (m,4H), 3.43 (m, 4H), 3.3 (m, 2H), 2.54 (m, 2H), 2.45 (m, 4H), 1.62 (m,4H), 1.54 (s, 3H, CH₃).

[1583] MS m/z 554.3 [M⁺+1].

Example 272 3-{3-[1-[3-Methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide

[1584]

[1585]¹H NMR (400MHz, DMSO-d₆) 5 13.51 (s, 1H, NH), 11.14 (s, 1H, NH),8.65 (t, 1H), 7.95 (m, 1H), 7.90 (m, 1H), 7.64 (t, 1H), 7.57 (m, 1H),7.39 (d, 1H), 7.23 (t, 1H), 6.94 (d, 1H), 6.83 (d, 1H), 6.81 (s, 1H),3.52 (m, 4H), 3.43 (m, 4H), 3.28 (m, 2H), 2.38 (m, 6H), 1.64 (m, 6H),1.55 (s, 3H).

[1586] MS m/z 568.3 [M⁺+1].

Example 273N-(2-Dimethylamino-ethyl)-3-{3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-benzamide

[1587]

[1588]¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (s, 1H, NH), 11.15 (s, 1H, NH),8.48 (t, 1H), 7.96 (m, 1H), 7.93 (m, 1H), 7.64 (t, 1H), 7.58 (m, 1H),7.39 (d, 1H), 7.23 (t, 1H), 6.94 (d, 1H), 6.83 (d, 1H), 6.80 (s, 1H),3.51 (m, 4H), 3.44 (m, 4H), 3.3 (m, 2H), 2.34 (t, 2H), 2.12 (s, 6H,2×CH₃), 1.55 (s, 3H, CH₃).

[1589] MS m/z 528.2 [M⁺+1].

Example 274N-(3-Dimethylamino-propyl)-3-{3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-benzamide

[1590]

[1591]¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (s, 1H, NH), 11.14 (s, 1H, NH),8.59 (t, 1H), 7.95 (m, 1H), 7.92 (m, 1H), 7.64 (t, 1H), 7.57 (m, 1H),7.39 (d, 1H), 7.23 (t, 1H), 6.94 (d, 1H), 6.83 (d, 1H), 6.81 (s, 1H),3.51 (m, 4H), 3.43 (m, 4H), 3.25 (m, 2H), 2.19 (t, 2H), 2.06 (s, 6H),1.60 (m, 2H), 1.55 (s, 3H, 2×CH₃).

[1592] MS m/z 542.3 [M⁺+1].

Example 275N-Methyl-3-{3-1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-N-(1-methyl-piperidin-4-yl)-benzamide

[1593]

[1594] MS m/z 568 [M⁺+1].

Example 2762-[2-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl]-N-(2-pyrrofldin-1-yl-ethyl)-acetamide

[1595]

[1596]¹H NMR (400 MHz, DMSO-d₆) δ 13.33 (s, NH, 1H), 10.98 (s, NH, 1H),7.49 (m, 2H), 7.41 (m, 1H), 7.31 (m, 2H), 7.17 (t, J=7.8 Hz, 1H), 6.93(d, J=7.4 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 6.57 (s, 1H), 5.91 (s, 1H),3.09 (m, 2H), 2.68 (m, 2H), 2.40 (m, 6H), 2.26 (s, 3H), 1.63 (m, 4H).

[1597] MS m/z 471 [M−1].

Example 277N-(2,4-Dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylmethyl)-2-{2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrol-3-yl}-acetamide

[1598]

[1599]¹H NMR (400 MHz, DMSO-d₆) δ 13.39 (s, NH,1H), 11.02 (s, NH, 1H),10.81 (br s, NH, 2H), 8.04 (m, 1H), 7.52 (m, 1H), 7.42 (m, 1H), 7.32 (m,2H), 7.19 (t, J=7.8 Hz, 1H), 6.96 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 6.81(dd, J=0.8 Hz, J=7.4 Hz, 1H), 6.62 (s, 1H), 5.93 (d, J=2.3 Hz, 1H), 5.18(s, 1H), 3.88 (m, 2H), 2.81 (d, J=11.3 Hz, 2H), 2.29 (s, 3H).

[1600] MS m/z 498 [M−1].

Example 2785-[4-(3-Amino-1H-indazol-5-yl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide

[1601]

[1602] MS m/z 510.5 [M−1].

Example 2795-[4-(3-Amino-1H-indazol-5-yl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1603]

[1604]¹H NMR (400MHz, DMSO-d₆) δ 13.46 (s, 1H, NH), 11.51 (s, 1H, NH),11.0 (s, 1H, NH), 7.73 (s, 1H), 7.41 (br s, 1H, NH), 7.35 (d, 1H),7.14-7.22 (m, 2H), 6.89 (d, 1H), 6.82 (d, 1H), 6.76 (s, 1H), 5.37 (br s,2H, NH₂), 2.99 (m, 2H), 2.54 (m, 2H), 2.44 (m, 2H), 2.35 (s, 3H, CH₃),1.7 (m, 4H), 1.62 (m, 2H), 1.4 (s, 3H, CH₃).

[1605] MS m/z 508.5 [M−1].

Example 2803-{3-[1-[3-Methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-benzoicacid

[1606]

[1607]¹H NMR (400 MHz, DMSO-d₆) δ 13.51 (s, 1H, NH), 11.14 (s, 1H, NH),8.05 (m, 1H), 7.95 (s, 1H), 7.7 (m, 2H), 7.40 (d, 1H), 7.22 (t, 1H),6.94 (d, 1H), 6.79 (s, 1H), 3.51 (m, 4H), 3.43 (m, 4H), 1.55 (s, 3H,CH₃).

[1608] MS m/z 458.4 [M⁺+1].

Example 2815-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide

[1609]

[1610]¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, 1H, NH), 11.06 (s, 1H, NH),7.58 (m, 1H), 7.46 (m, 1H), 7.25-7.35 (m, 3H), 7.18 (t, 1H), 6.93 (d,1H), 6.78 (d, 1H), 6.77 (s, iH), 3.68 (m, 1H), 3.36 (m, 2H), 3.28 (dd,1H), 3.1 (dd, 1H), 2.52 (m, 4H), 2.37 (s, 3H, CH₃), 1.71 (s, 3H, CH₃),1.66 (m, 4H).

[1611] MS m/z 503.4 [M⁺+1].

Example 2823-[1-[4-(3-Diethylamino-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1612]

[1613] MS m/z 499 [M−1].

Example 2833-[1-[3-(3-Diethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1614]

[1615] MS m/z 485 [M−1].

Example 2843-[1-{4-[2-(3-Diethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1616]

[1617] MS m/z 513 [M−1].

Example 285 3-[1-{3-[2-(3-Diethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1618]

[1619] MS m/z 499 [M−1].

Example 2865-[4-(2,4-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1620]

[1621]¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, NH, 1H), 11.09 (s, NH, 1H),7.49 (m, 3H), 7.30 (m, 1H), 7.20 (t, J=7.8 Hz, 1H), 6.96 (d, J=7.8 Hz,1H), 6.81 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.59 (s, 1H), 3.27 (m, 2H), 2.48(m, 6H), 2.36 (s, 3H), 1.74 (s, 3H), 1.64 (m, 4H).

[1622] MS m/z 489 [M−1].

Example 2872-[4-(2,4-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1623]

[1624]¹H NMR (400 MHz, DMSO-d₆) δ 13.79 (s, NH,1H), 11.18 (s, NH, 1H),7.93 (m, 1H), 7.88 (m, 1H), 7.37 (m, 1H), 7.21 (m, 2H), 7.13 (m, 1H),6.95 (d, J=6.6 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.37 (m, 1H), 3.10 (m,2H), 2.39 (m, 6H), 2.30 (s, 3H), 1.67 (m, 4H), 1.59 (m, 2H).

[1625] MS m/z 489 [M−1].

Example 288 4-(2,4-Difluoro-phenyl)-3-[1-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1626]

[1627]¹H NMR (400 MHz, DMSO-d₆) δ 13.45 (s, NH, 1H), 11.09 (s, NH, 1H),7.50 (m, 2H), 7.29 (m, 1H), 7.20 (t, J=7.6 Hz, 1H), 6.96 (dd, J=0.8 Hz,J=7.8 Hz, 1H), 6.81 (dd, J=0.8 Hz, J=7.4 Hz, 1H), 6.57 (s, 1H), 3.28 (m,4H), 2.27 (m, 4H), 2.23 (s, 3H), 2.16 (s, 3H), 1.62 (s, 3H).

[1628] MS m/z 475 [M−1].

Example 289 4-(2,4-Difluoro-phenyl)-3-[1-[5-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1629]

[1630]¹H NMR (400 MHz, DMSO-d₆) δ 13.63 (s, NH, 1H), 11.14 (s, NH, 1H),7.40 (m, 1H), 7.29 (m, 1H), 7.20 (t, J=7.8 Hz, 1H), 7.16 (m, 1H), 6.95(dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.82 (s, 1H), 6.76 (dd, J=0.8 Hz, J=7.4Hz, 1H), 6.08 (d, J=2.3 Hz, 1H), 4.09 (m, 1H), 3.58 (m, 1H), 2.87 (m,2H), 2.45 (m, 4H), 2.31 (s, 3H), 2.19 (m, 1H), 1.82 (m, 1H), 1.66 (m,5H), 1.21 (m, 2H).

[1631] MS m/z 515 [M−1].

Example 290 4-(3-Chloro-phenyl)-3-[1-[4-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1632]

[1633]¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, NH, 1H), 11.14 (s, NH, 1H),7.59 (m, 4H), 7.42 (m, 1H), 7.21 (t, J=7.8 Hz, 1H), 6.93 (dd, J=0.8 Hz,J=7.8 Hz, 1H), 6.85 (s, 1H), 6.81 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 4.92 (m,1H), 4.24 (m, 1H), 3.58 (m, 1H), 3.50 (m, 2H), 3.29 (m, 1H), 1.85 (m,1H), 1.77 (m, 1H), 1.74 (s, 3H).

[1634] MS m/z 446 [M−1].

Example 291 4-(3-Chloro-phenyl)-3-[I-[3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1635]

[1636]¹H NMR (400 MHz, DMSO-d₆) (2 conformational isomer) δ 13.65 (s,NH, 1H), 11.08 (br s, NH, 1H), 7.44 (m, 2H), 7.38 (m, 1H), 7.32 (m, 1H),7.19 (m, 2H), 6.91 (d, J=7.8 Hz, 1H), 6.75 (dd, J=0.8 Hz, J=7.4 Hz, 1H),6.20 (m, 1H), 4.82 (m, 1H), 4.31 (m, 0.5H), 4.13 (m, 0.5H), 3.30 (m,4H), 2.31 (s, 3H), 1.82 (m, 2H).

[1637] MS m/z 446 [M−1].

Example 2924-(2-Fluoro-phenyl)-3-[1-[4-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1638]

[1639]¹H NMR (400MHz, DMSO-d₆) δ 13.52 (s, NH, 1H), 11.08 (br s, NH,1H), 7.56 (m, 2H), 7.43 (m, 3H), 7.23 (t, J=7.8 Hz, 1H), 6.95 (d, J=7.8Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.71 (s, 1H), 4.92 (m, 1H), 4.22 (m,1H), 3.58 (m, 1H), 3.94 (m, 1H), 3.28 (m, 2H), 1.86 (m, 1H), 1.72 (m,1H), 1.68 (s, 3H).

[1640] MS m/z 430 [M−1].

Example 293 4-(3-Fluoro-phenyl)-3-[1-[4-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1641]

[1642]¹H NMR (400 MHz, DMSO-d₆) (2 conformational isomer) δ 13.39 (s,NH, 1H), 11.04 (s, NH, 1H), 7.58 (m, 1H), 7.29 (m, 3H), 7.18 (t, J=7.8Hz, 1H), 6.93 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 6.79 (dd, J=0.8 Hz, J=7.8Hz, 1H), 6.75 (s, 1H), 4.95 (m, 0.5H), 4.85 (m, 0.5H), 4.29 (m, 0.5H),4.15 (m, 0.5H), 3.45 (m, 1H), 3.25 (m, 3H), 2.22 (s, 3H), 1.81 (m, 2H),1.59 (s, 3H).

[1643] MS m/z 444 [M−1].

Example 294 4-(3-Fluoro-phenyl)-3-[1-{4-[2-((R)-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1644]

[1645]¹H NMR (400 MHz, DMSO-d₆) (2 conformational isomer) δ 13.29 (s,NH, 1H), 10.92 (s, NH, 1H), 7.57 (m, 1H), 7.28 (m, 3H), 7.12 (t, J=7.4Hz, 1H), 6.92 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.76 (dd, J=0.8 Hz, J=7.6Hz, 1H), 6.74 (s, 1H), 4.99 (d, J=3.5 Hz, 0.5H), 4.88 (d, J=3.5 Hz,0.5H), 4.29 (m, 0.5H), 4.21 (m, 0.5H), 3.54 (m, 1H), 3.37 (m, 1H), 3.25(m, 2H), 2.20 (s, 3H), 1.82 (m, 2H), 1.52 (s, 3H).

[1646] MS m/z 458 [M−1].

Example 2954-(2,6-Difluoro-phenyl)-3-[1-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1647]

[1648]¹H NMR (400 MHz, DMSO-d₆) δ 13.49 (s, NH, 1H), 10.19 (s, NH, 1H),7.64 (m, 1H), 7.40 (d, J=3.1 Hz, 1H), 7.35 (m, 2H), 7.26 (t, J=7.8 Hz,1H), 6.99 (dd, j=0.8 Hz, J=7.8 Hz, 1H), 6.89 (d, J=7.0 Hz, 1H), 6.29 (s,1H), 3.44 (m, 4H), 2.23 (m, 4H), 2.15 (s, 3H), 1.62 (s, 3H).

[1649] MS m/z 461 [M−1].

Example 296 4-(2,6-Difluoro-phenyl)-3-[1-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1650]

[1651] MS m/z 475 [M−1].

Example 297 4-(3-Chloro-phenyl)-3-[1 -[5-methyl-3-(4-methyl-piperazine1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylideijel-1,3-dihydro-indol-2-one

[1652]

[1653]¹H NMR (400 MHz, DMSO-d₆) δ 13.63 (s, NH, 1H), 11.09 (br s, NH,1H), 7.44 (m, 2H), 7.37 (s, 1H), 7.32 (m, 1H), 7.18 (t, J=7.8 Hz, 1H),6.94 (s, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.75 (d, J=7.4 Hz, 1H), 6.06 (d,J=2.0 Hz, 1H), 3.33 (m, 2H), 3.22 (m, 2H), 2.30 (s, 3H), 2.24 (m, 2H),2.16 (s, 3H), 2.11 (m, 2H).

[1654] MS m/z 459 [M−1].

Example 298 4-(3-Fluoro-phenyl)-3-[1-[5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1655]

[1656]¹H NMR (400 MHz, DMSO-d₆) δ 13.61 (s, NH, 1H), 11.12 (s, NH, 1H),7.46 (m, 1H), 7.19 (m, 4H), 6.94 (s, 1H), 6.91 (dd, J=1.2 Hz, J=7.8 Hz,1H), 6.75 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 6.05 (d, J=2.3 Hz, 1H), 3.21 (m,4H), 2.32 (s, 3H), 2.25 (m, 2H), 2.17 (s, 3H), 2.12 (m, 2H).

[1657] MS m/z 445 [M⁺+1].

Example 2995-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1658]

[1659]¹H NMR (400 MHz, DMSO-d₆) δ 13.44 (s, NH, 1H), 10.12 (s, NH, 1H),7.63 (m, 1H), 7.50 (m, 1H), 7.34 (m, 2H), 7.22 (t, J=7.8 Hz, 1H), 6.97(dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.59 (s, 1H), 3.28(m, 2H), 2.52 (m, 6H), 2.37 (s, 3H), 1.68 (s, 3H), 1.65 (m, 4H).

[1660] MS m/z 489 [M−1].

Example 3002-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1661]

[1662]¹H NMR (400 MHz, DMSO-d₆) δ 13.79 (s, NH, 1H), 11.17 (br s, NH,1H), 7.91 (m, 1H), 7.85 (s, 1H), 7.48 (m, 1H), 7.22 (t, J=7.4 Hz, 1H),7.14 (m, 2H), 6.97 (d, J=7.8 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 6.35 (m,1H), 3.61 (m, 2H), 2.41 (m, 6H), 2.30 (s, 3H), 1.68 (m, 4H), 1.58 (m,2H).

[1663] MS m/z 489 [M⁻−1]

Example 3014-(2,6-Difluoro-phenyl)-3-[1-[3,5-dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1664]

[1665] MS m/z 529 [M−1].

Example 3022-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid 12-(4-acetyl-piperazin-1-yl)-ethyl]-amide

[1666]

[1667]¹H NMR (400 MHz, DMSO-d₆) δ 13.80 (s, NH, 1H), 11.13 (s, NH, 1H),7.84 (s, 1H), 7.75 (m, 1H), 7.43 (m, 1H), 7.34 (m, 1H), 7.25 (m, 2H),7.20 (t, J=7.8 Hz, 1H), 6.94 (d, J=6.6 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H),6.35 (s, 1H), 3.42 (m, 4H), 3.15 (m, 2H), 2.39 (m, 6H), 2.29 (s, 3H),1.98 (s, 3H).

[1668] MS m/z 514 [M−1].

Example 3032-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid [2-(4-acetyl-piperazin-1-yl)-ethyl]-amide

[1669]

[1670]¹H NMR (400 MHz, DMSO-d₆) δ 13.80 (s, NH, 1H), 11.08 (s, NH, 1H),7.99 (s, 1H), 7.75 (m, 1H), 7.43 (m, 1H), 7.17 (m, 4H), 6.91 (d, J=6.6Hz, 1H), 6.75 (d, J=6.6 Hz, 1H), 6.35 (s, 1H), 3.42 (m, 4H), 3.15 (m,2H), 2.39 (m, 6H), 2.29 (s, 3H), 1.98 (s, 3H).

[1671] MS m/z 514 [M−1].

Example 3045-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid [2-(4-acetyl-piperazin-1-yl)-ethyl]-amide

[1672]

[1673]¹H NMR (400 MHz, DMSO-d₆) δ 13.53 (s, NH, 1H), 11.17 (s, NH, 1H),8.28 (br m, 1H), 7.83 (br s, 1H), 7.58 (m, 1H), 7.46 (m, 2H), 7.40 (t,J=7.8 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 6.96 (dd, J=0.8 Hz, J=7.4 Hz,1H), 6.83 (d, J=7.8 Hz, 1H), 6.72 (s, 1H), 4.38 (m, 1H), 3.96 (m,-1H),3.53 (m, 5H), 3.20 (m, 2H), 2.98 (m, 3H), 2.01 (s, 3H), 1.80 (s, 3H).

[1674] MS m/z 514 [M−1].

Example 3055-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]4-methyl-1H-pyrrole-3-carboxylicacid (2-piperidin-1-yl-ethyl)-amide

[1675]

[1676]¹H NMR (400 MHz, DMSO-d₆) δ 13.47 (s, NH, 1H), 11.11 (br s, NH,1H), 7.71 (m, 1H), 7.66 (d, J=3.5 Hz, 1H), 7.56 (m, 1H), 7.44 (m, 3H),7.22 (t, J=7.4 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H),6.71 (s, 1H), 3.23 (m, 2H), 2.32 (m, 6H), 1.75 (s, 3H), 1.45 (m, 4H),1.34 (m, 2H).

[1677] MS m/z 471 [M−1].

Example 306

[1678]2-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-piperidin-1-yl-ethyl)-amide

[1679]¹H NMR (400 MHz, DMSO-d₆) δ 13.69 (s, NH, 1H), 11.11 (s, NH, 1H),7.99 (s, 1H), 7.70 (m, 1H), 7.43 (m, 1H), 7.37 (m, 2H), 7.30 (d, J=7.4Hz, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.75 (d, J=7.8Hz, 1H), 6.36 (s, 1H), 3.15 (m, 2H), 2.38 (m, 4H), 2.31 (m, 2H), 2.29(s, 3H), 1.50 (m, 4H), 1.38 (m, 2H).

[1680] MS m/z 487 [M−1].

Example 3075-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-piperidin-1-yl-ethyl)-amide

[1681]

[1682]¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, NH, 1H), 11.12 (s, NH, 1H),7.75 (m, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.57 (m, 2H), 7.52 (s, 1H), 7.40(m, 1H), 7.21 (t, J=7.4 Hz, 1H), 6.92 (d, J=7.0 Hz, 1H), 6.85 (s, 1H),6.80 (d, J=7.8 Hz, 1H), 3.25 (m, 2H), 2.41 (m, 6H), 1.84 (s, 3H), 1.48(m, 4H), 1.36 (m, 2H).

[1683] MS m/z 487 [M−1].

Example 3082-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide

[1684]

[1685]¹H NMR (400MHz, DMSO-d₆) 6 13.82 (s, NH, 1H), 11.18 (s, NH, 1H),8.02 (s, 1H), 7.84 (m, 1H), 7.40 (m, 3H), 7.31 (m, 1H), 7.19 (t, 1H),6.91 (d, 1H), 6.76 (d, 1H), 6.40 (s, 1H), 4.68 (m, 1H), 3.64 (m, 1H),3.29 (m, 1H), 2.84 (m, 1H), 2.45 (m, 4H), 2.34 (m, 2H), 2.30 (s, 3H),1.69 (m, 4H).

[1686] MS m/z 503 [M−1].

Example 3092-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide

[1687]

¹H NMR (400 MHz, DMSO-d₆) δ 13.84 (s, NH, 1H),l 1.10 (br s, NH, 1H),8.01 (s, 1H), 7.85 (m, 1H), 7.42 (m, 1H), 7.15 (m, 4H), 6.91 (d, J=7.8Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.39 (s, 1H), 4.69 (m, 1H), 3.62 (m,1H), 3.26 (m, 1H), 2.92 (m, 1H), 2.46 (m, 4H), 2.32 (m, 2H), 2.29 (s,3H), 1.68 (m, 4H).

[1688] MS m/z 487 [M−1].

Example 3105-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide

[1689]

[1690]¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, NH,1H), 11.12 (s, NH, 1H),7.82 (m, 1H), 7.71 (d, J=3.1 Hz, 1H), 7.58 (m, 2H), 7.52 (s, 1H), 7.41(m, 1H), 7.21 (t, J=7.8 Hz, 1H), 6.92 (dd, J=0.8 Hz, J 7.8 Hz, 1H), 6.85(s, 1H), 6.80 (dd, J=0.8 Hz, J=7.4 Hz, 1H), 4.73 (m, 1H), 3.66 (m, 1H),3.28 (m, 2H), 3.03 (m, 1H), 2.44 (m, 4H), 2.32 (m, 1H), 1.82 (s, 3H),1.62 (m, 4H).

[1691] MS m/z 503 [M−1].

Example 3115-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide

[1692]

[1693]¹H NMR (400 MHz, DMSO-d₆) δ 13.47 (s, NH, 1H), 11.13 (s, NH, 1H),7.81 (m, 1H), 7.70 (d, J=3.1 Hz, 1H), 7.57 (m, 1H), 7.42 (m, 3H), 7.21(t, J=7.8 Hz, 1H), 6.95 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 6.83 (dd, J=0.8Hz, J=7.4 Hz, 1H), 6.71 (s, 1H), 4.72 (m, 1H), 3.65 (m, 1H), 3.29 (m,2H), 3.03 (m, 1H), 2.44 (m, 4H), 2.32 (m, 1H), 1.79 (s, 3H), 1.63 (m,4H).

[1694] MS m/z 487 [M−1].

Example 3125-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide

[1695]

[1696]¹H NMR (400 MHz, DMSO-d₆) δ 13.47 (s, NH, 1H), 11.06 (s, NH, 1H),7.56 (m, 2H), 7.51 (s, 1H), 7.46 (m, 1H), 7.39 (m, 1H), 7.18 (t, J=7.8Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 6.76 (s, 1H),4.72 (m, 1H), 3.68 (m, 1H), 3.28 (m, 1H), 3.11 (m, 1H), 2.36 (m, 5H),1.74 (s, 3H), 1.65 (m, 5H).

[1697] MS m/z 517 [M−1].

Example 3134-(3-Chloro-phenyl)-3-[1-[4-((S)-3-hydroxy-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1698]

[1699]¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, NH, 1H), 11.04 (s, NH, 1H),7.56 (m, 2H), 7.52 (m, 1H), 7.39 (m, 1H), 7.17 (t, J=7.4 Hz, 1H), 6.92(d, J=7.8 Hz, 1H), 6.78 (d, J=7.0 Hz, 1H), 6.74 (s, 1H), 4.89 (m, 1H),4.21 (m, 1H), 3.45 (m, 2H), 3.25 (m, 1H), 3.04 (m, 1H), 2.22 (s, 3H),1.80 (m, 2H), 1.60 (s, 3H).

[1700] MS m/z 460 [M−1].

Example 3144-(3-Chloro-phenyl)-3-[1-[4-((S)-3-hydroxy-pyrrolidine-1-carbonyl)-3-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1701]

[1702]¹H NMR (400 MHz, DMSO-d₆) δ 13.49 (s, NH, 1H), 11.13 (s, NH, 1H),7.56 (m, 4H), 7.41 (m, 1H), 7.17 (t, J=7.8 Hz, 1H), 6.92 (dd, J=0.8 Hz,J=7.8 Hz, 1H), 6.85 (s, 1H), 6.80 (dd, J=0.8 Hz, J=7.4 Hz, 1H), 6.74 (s,1H), 4.91 (m, 1H), 4.24 (m, 1H), 3.58 (m, 1H), 3.46 (m, 2H), 3.28 (m,1H), 1.86 (m, 1H), 1.78 (m, 1H), 1.74 (s, 3H).

[1703] MS m/z 446 [M−1].

Example 3154-(3-Chloro-phenyl)-3-[1-[3-((S)-3-hydroxy-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene-1,3-dihydro-indol-2-one

[1704]

[1705]¹H NMR (400 MHz, DMSO-d₆) δ 13.64 (s, NH, 1H), 11.12 (s, NH, 1H),7.44 (m, 2H), 7.38 (m, 1H), 7.32 (m, 1H), 7.19 (m, 2H), 6.91 (d, J=7.8Hz, 1H), 6.75 (d, J=7.0 Hz, 1H), 6.18 (m, 1H), 4.91 (m, 1H), 4.22 (m,1H), 3.40 (m, 2H), 3.21 (m, 2H), 2.30 (s, 3H), 1.81 (m, 2H).

[1706] MS m/z 446 [M−1].

Example 3164-(2-Fluoro-phenyl)-3-[l1-[4-((S)-3-hydroxy-pyrrolidine-1-carbonyl)-3-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1707]

[1708]¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, NH, 1H), 1I 1. 15 (s, NH,1H), 7.5 6 (m, 1H), 7.43 (m, 3H), 7.23 (t, J=7.8 Hz, 1H), 6.95 (dd,J=0.8 Hz, J=7.8 Hz, 1H), 6.83 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.71 (s,1H), 4.92 (m, 1H), 4.22 (m, 1H), 3.58 (m, 1H), 3.45 (m, 2H), 3.28 (m,1H), 1.85 (m, 1H), 1.75 (m, 1H), 1.69 (s, 3H).

[1709] MS m/z 430 [M−1].

Example 3174-(3-Fluoro-phenyl)-3-[1-[4-((S)-3-hydroxy-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1710]

[1711]¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, NH, 1H), 11.04 (s, NH, 1H),7.57 (m, 1H), 7.31 (m, 3H), 7.17 (t, J=7.8 Hz, 1H), 6.92 (d, J=7.8 Hz,1H), 6.78 (d, J=7.8 Hz, 1H), 6.75 (s, 1H), 4.90 (m, 1H), 4.20 (m, 1H),3.47 (m, 2H), 3.24 (m, 1H), 3.04 (m, 1H), 2.21 (s, 3H), 1.80 (m, 2H),1.58 (s, 3H).

[1712] MS m/z 444 [M−1].

Example 3184-(3-Fluoro-phenyl)-3-[1-{4-[2-((S)-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1713]

[1714]¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, NH, 1H), 10.92 (s, NH, 1H),7.57 (m, 1H), 7.28 (m, 3H), 7.13 (t, J=7.4 Hz, 1H), 6.91 (d, J=7.0 Hz,1H), 6.76 (m, 2H), 4.92 (m, 1H), 4.22 (m, 1H), 3.54 (m, 2H), 3.28 (s,2H), 3.22 (m, 2H), 2.19 (s, 3H), 1.81 (m, 2H), 1.52 (s, 3H).

[1715] MS m/z 458 [M−1].

Example 3194-(3-Fluoro-phenyl)-3-[1-[4-(4-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1716]

[1717]¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (s, NH, 1H), 10.94 (s, NH, 1H),7.57 (m, 1H), 7.28 (m, 3H), 7.13 (t, 1H), 6.91 (dd, 1H), 6.76 (m, 2H),4.48 (d, 1H), 3.38 (m, 1H), 3.11 (s, 2H), 2.55 (m, 2H), 2.22 (s, 3H),1.89 (m, 2H), 1.62 (m, 2H), 1.60 (s, 3H), 1.28 (m, 2H).

[1718] MS m/z 444 [M−1].

Example 3203-[1-(3,5-Dimethyl-4-morpholin-4-ylmethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1719]

[1720]¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (s, NH, 1H), 10.96 (s, NH, 1H),7.57 (m, 1H), 7.28 (m, 3H), 7.13 (t, J=7.4 Hz,1H), 6.90 (dd, J=0.8 Hz,J=7.4 Hz,1H), 6.76 (m, 2H), 3.47 (m, 4H), 3.16 (s, 2H), 2.25 (s, 3H),2.22 (m, 4H), 1.62 (s, 3H).

[1721] MS m/z 430 [M−1].

Example 3212-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4,5,6,7-tetrahydro-1H-indole-3-carboxylicacid

[1722]

[1723]¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s, NH, 1H), 8.05 (s, 1H), 7.44(m, 1H) , 7.20 (m, 4H), 6.92 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.75 (dd,J=0.8 Hz, J=7.4 Hz, 1H), 2.62 (m, 4H), 1.68 (m, 4H).

[1724] MS m/z 401 [M−1].

Example 3222-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4,5,6,7-tetrahydro-1H-indole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1725]

[1726]¹H NMR (400 MHz, DMSO-d₆) δ 13.53 (s, NH, 1H), 11.06 (s, NH, 1H),7.52 (m, 1H), 7.42 (m, 1H), 7.36 (s, 1H), 7.17 (m, 4H), 6.90 (d, J=7.4Hz, 1H), 6.75 (d, J=7.4 Hz, 1H), 3.27 (m, 2H), 3.04 (m, 2H), 2.64 (m,2H), 2.39 (m, 6H), 1.64 (m, 10H).

[1727] MS m/z 511 [M−1].

Example 3234-(3-Fluoro-phenyl)-3-[1-[3-(3-hydroxy-pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1728]

[1729]¹H NMR (400 MHz, DMSO-d₆) δ 13.44 (s, NH, 1H), 11.07 (s, NH, 1H),1H) , 7.25 (m, 1H), 7.17 (m, 3H), 6.90 (d, J=7.8 Hz, 1H), 6.78 (m, 1H),6.73 0.8 Hz, J =7.8 Hz, 1H), 4.88 (m, 1H), 4.20 (m, 1H), 3.35 (m, 2H),3.18 (m, 6 (m, 1H), 2.65 (m, 2H), 2.28 (m, 2H), 1.70 (m, 6H).

[1730] MS m/z 470[M−1].

Example 3244-(2-Fluoro-phenyl)-3-[1-{3-[(S)-2-(4-hydroxy-piperidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1731]

[1732] MS m/z 527 [M−1].

Example 3254-(2-Fluoro-phenyl)-3-[1-{3-[(S)-2-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1733]

[1734] MS m/z 513 [M−1].

Example 3264-(3-Fluoro-phenyl)-3-[1-{4-[(S)-2-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-3,5-dimethyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1735]

[1736]¹H NMR (400 MHz, DMSO-d₆) δ 13.31 (s, NH, 1H), 10.62 (s, NH, 1H),7.56 (m, 1H), 7.24 (m, 3H), 7.16 (t, J=7.8 Hz, 1H), 6.94 (d, J=7.8 Hz,1H), 6.81 (s, 1H), 6.78 (d, J=6.8 Hz, 1H), 4.15 (m, 2H), 4.05 (m, 1H),2.88 (m, 4H), 2.76 (m, 1H), 2.58 (m, 2H), 2.38 (m, 2H), 2.24 (s, 3H),1.88 (m, 4H), 1.72 (m, 1H), 1.64 (s, 3H), 1.53 (m, 1H).

[1737] MS m/z 527 [M−1].

Example 3274-(3-Fluoro-phenyl)-3-[1-{3-[(S)-2-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1738]

[1739] MS m/z 513 [M⁻1].

Example 3282-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid {2-[4-(2-hydroxy-acetyl)-piperazin-1-yl]-ethyl}-amide

[1740]

[1741]¹H NMR (400 MHz, DMSO-d₆) δ 13.79 (s, NH, 1H), 11.12 (s, NH, 1H),7.99 (s, 1H), 7.76 (m, 1H), 7.45 (m, 1H), 7.16 (m, 4H), 6.91 (d, 1H),6.75 (d, 1H), 6.36 (s, 1H), 4.52 (t, 1H), 4.07 (d, 2H), 3.46 (m, 2H),3.36 (m, 2H), 3.16 (m, 2H), 2.39 (m, 6H), 2.29 (s, 3H).

[1742] MS m/z 530 [M−1]

Example 3294-(2,6-Difluoro-phenyl)-3-[1-[4-(3-piperidin-1-yl-propionyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-blazepin-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1743]

[1744]4-(3-Piperidin-1-yl-propionyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde(80 mg, 0.26 mmol) was condensed with4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one (61 mg, 0.25 mmol) andpiperidine (1 drop) in ethanol (3 mL) at rt for over the weekend. Theprecipitate was filtered, washed with ethanol and dried to give 80 mg ofthe titled compound as a yellow solid.

[1745]¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, 1H, NH), 11.14 (s, 1H, NH),7.62 (m, 1H), 7.25 (m, 1H), 6.99 (d, 1H), 6.87 (d, 1H), 6.37 (s, 1H),6.21 (s, 1H), 3.47 (m, 2H), 2.72 (m, 2H), 2.38 (m, 2H), 2.3 (m, 2H),2.13 (m, 4H), 1.68 (m, 2H), 1.60 (m, 2H), 1.37 (m, 4H), 1.31 (m, 2H).

[1746] MS m/z 531.2 [M⁺+1].

Example 3305-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-(3-methanesulfonyl-propyl)-2-methyl-1H-pyrrole-3-carboxylicacid

[1747]

[1748]¹H NMR (400 MHz, DMSO-d₆) δ 13.79 (s, NH, 1H), 12.22 (s, 1H),11.17 (s, NH, 1H), 7.60 (m, 1H), 7.40 (m, 1H), 7.31 (m, 2H), 7.21 (t, J=7.8 Hz, 1H), 6.94 (d, J=7.0 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 6.77 (s,1H), 2.92 (s, 3H), 2.69 (m, 2H), 2.48 (s, 3H), 2.32 (m, 2H), 1.61 (m,2H).

[1749] MS m/z 481 [M−1].

Example 3315-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-(3-methanesulfonyl-propyl)-2-methyl-1H-pyrrole-3-carboxylicacid

[1750]

[1751]¹H NMR (400 MHz, DMSO-d₆) δ 13.80 (s, NH, 1H), 12.22 (s, 1H),11.17 (s, NH, 1H), 7.62 (m, 2H), 7.48 (m, 2H), 7.21 (t, J=7.8 Hz, 1H),6.94 (d, J=7.8 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.75 (s, 1H), 2.94 (s,3H), 2.73 (m, 2H), 2.47 (s, 3H), 2.34 (m, 2H), 1.63 (m, 2H).

[1752] MS m/z 497 [M⁻1].

Example 3324-(3-Fluoro-phenyl)-3-[1-[4-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3-(3-methanesulfonyl-propyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1753]

[1754]¹H NMR (400 MHz, DMSO-d₆) δ 13.47 (s, NH, 1H), 11.10 (s, NH, 1H),7.59 (m, 1H), 7.38 (m, 1H), 7.29 (m, 2H), 7.19 (t, J=7.8 Hz, 1H), 6.92(d, J=7.4 Hz, 1H) , 6.78 (d, J=7.8 Hz, 1H), 6.71 (d, J=0.8 Hz, 1H), 4.92(m, 1H), 4.22 (m, 1H), 3.48 (m, 2H), 3.21 (m, 2H), 2.89 (s, 3H), 2.71(m, 2H), 2.24 (s, 3H), 2.08 (m, 2H), 1.82 (m, 2H), 1.52 (m, 2H).

[1755] MS m/z 550 [M−1].

Example 3334-(3-Fluoro-phenyl)-3-[1-[3-(3-methanesulfonyl-propyl)-5-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1756]

[1757]¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (s, NH, 1H), 11.10 (s, NH, 1H),7.60 (m, 1H), 7.40 (m, 1H), 7.31 (m, 2H), 7.19 (t, J=7.8 Hz, 1H), 6.93(d, J=7.4 Hz, 1H), 6.78 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.72 (s, 1H), 3.31(m, 4H), 2.92 (s, 3H), 2.78 (m, 2H), 2.30 (m, 4H), 2.20 (s, 3H), 2.18(s, 3H), 2.05 (m, 2H), 1.51 (m, 2H).

[1758] MS m/z 563 [M−1].

Example 3344-(4-Chloro-phenyl)-3-[1-[3-(3-methanesulfonyl-propyl)-5-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1759]

[1760]¹H NMR (400MHz, DMSO-d₆) δ 13.53 (s, NH, 1H), 11.10 (s, NH, 1H),7.62 (m, 2H), 7.44 (m, 2H), 7.19 (t, J=7.8 Hz, 1H), 6.93 (d, J=7.8 Hz,1H), 6.77 (dd, J=0.8 Hz, J=7.4 Hz, 1H), 6.71 (s, 1H), 3.34 (m, 4H), 2.92(s, 3H), 2.78 (m, 2H), 2.28 (m, 4H), 2.21 (s, 3H), 2.15 (s, 3H), 2.10(m, 2H), 1.55 (m, 2H).

[1761] MS m/z 581 [M⁺+1].

Example 3353-[1-[3-((cis)-3,5-Dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethoxy)-phenyl]-1,3-dihydro-indol-2-one

[1762]

[1763]¹H NMR (400 MHz, DMSO-d₆) δ 13.63 (s, NH, 1H), 11.09 (s, NH, 1H),7.30 (m, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.98 (s, 1H), 6.90 (m, 4H), 6.73(dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.03 (d, J=2.0 Hz, 1H), 4.13 (m, 1H), 3.99(m, 2H), 3.70 (m, 2H), 3.38 (m, 1H), 3.06 (m, 1H), 2.44 (m, 2H), 2.30(s, 3H), 2.18 (m, 2H), 1.81 (m, 1H), 1.04 (m, 3H), 0.81 (m, 3H).

[1764] MS m/z 499 [M−1].

Example 3363-[1-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethoxy)-phenyl]-1,3-dihydro-indol-2-one

[1765]

[1766]¹H NMR (400 MHz, DMSO-d₆) δ 13.44 (s, NH, 1H), 11.01 (s, NH, 1H),7.43 (t, J=8.2 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 7.03 (m, 1H), 6.95 (m,2H), 6.89 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 6.86 (s, 1H), 6.78 (dd, J=0.8Hz, J=7.4 Hz, 1H), 4.84 (t, J=5.5 Hz, 1H), 3.98 (t, J=5.1 Hz, 2H), 3.67(m, 2H), 3.41 (m, 4H), 2.28 (m, 4H), 2.21 (s, 3H), 2.15 (s, 3H), 1.57(s, 3H).

[1767] MS m/z 499 [M−1].

Example 3374-[3-(2-Hydroxy-ethoxy)-phenyl]-3-[1-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1768]

[1769]¹H NMR (400 MHz, DMSO-d₆) δ 13.44 (s, NH, 1H), 11.04 (s, NH, 1H),7.40 (t, J=8.2 Hz, 1H), 7.31 (d, J=3.1 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H),7.00 (m, 1H), 6.91 (m, 2H), 6.87 (s, 1H), 6.85 (d, J=7.4 Hz, 1H), 6.74(d, J=7.8 Hz, 1H), 4.79 (t, J=5.5 Hz, 1H), 3.94 (t, J=5.1 Hz, 2H), 3.63(m, 2H), 3.38 (m, 4H), 2.19 (m, 4H), 2.10 (s, 3H), 1.59 (s, 3H).

[1770] MS m/z 485 [M−1].

Example 3385-[4-[3-(2-Hydroxy-ethoxy)-phenyl]-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1771]

[1772] 4-[3-(2-Hydroxy-ethoxy)-phenyl]-1,3-dihydro-indol-2-one (0.25 mg)was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-pyrrolidin-1-yl-ethyl)-amide (0.25 mmol) and pyrrolidine (2 drops) inethanol (2 mL) at rt for overnight to give 76.4 mg (60%) of the titledcompound as a yellow solid.

[1773]¹H NMR (400 MHz, DMSO-d₆) δ 13.42 (s, NH, 1H), 10.97 (s, 1H, NH),7.38 (m, 2H), 7.11 (t, 1H), 6.99 (m, 1H), 6.85 (dd, 1H), 6.82 (s, 1H),6.73 (dd, 1H), 4.81 (m, 1H), 3.94 (t, 2H), 3.63 (m, 2H), 3.22 (m, 4H),2.45 (m, 4H), 2.31 (s, 3H, CH₃), 1.65 (s, 3H, CH₃), 1.61 (m, 4H).

[1774] MS m/z 515.6 [M⁺+1].

Example 3393-[1-[3,5-Dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-[3-(2-hydroxy-ethoxy)-phenyl]-1,3-dihydro-indol-2-one

[1775]

[1776]¹H NMR (400 MHz, DMSO-d₆) δ 13.42 (s, NH, 1H), 11.02 (br s, NH,1H), 7.43 (t, J =7.8 Hz, 1H), 7.16 (t, J =7.8 Hz, 1H), 7.03 (m, 1H),6.95 (m, 2H), 6.89 (d, J=7.8 Hz, 1H), 6.85 (s, 1H), 6.78 (d, J =7.4 Hz,1H), 4.83 (m, 1H), 3.97 (m, 2H), 3.67 (m, 2H), 3.18 (m, 1H), 2.93 (m,2H), 2.43 (m, 4H), 2.21 (s, 3H), 2.14 (m, 1H), 1.75 (m, 2H), 1.63 (m,6H), 1.56 (s, 3H), 1.21 (m, 1H).

[1777] MS m/z 553 [M−1].

Example 3404-[3-(2-Hydroxy-ethoxy)-phenyl]-3-[1-[5-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1778]

[1779]¹H NMR (400 MHz, DMSO-d₆) δ 13.60 (s, NH, 1H), 11.08 (s, NH, 1H),7.30 (t, J=7.8 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.95 (m, 2H), 6.87 (m,3H), 6.73 (d, J=7.4 Hz, 1H), 6.03 (d, J=2.3 Hz, 1H), 4.86 (m, 1H), 4.02(m, 1H), 3.97 (m, 2H), 3.68 (m, 2H), 3.45 (m, 1H), 2.75 (m, 2H), 2.46(m, 4H), 2.29 (s, 3H), 2.13 (m, 1H), 1.79 (m, 1H), 1.66 (m, 6H), 1.15(m, 1H) .

[1780] MS m/z 539 [M-l].

Example 3414-[3-(2-Hydroxy-ethoxy)-phenyl]-3-l1-[4-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1781]

[1782]¹H NMR (400 MHz, DMSO-d₆) δ 13.38 (s, NH, 1H), 11.00 (s, NH, 1H),7.43 (t, J=8.2 Hz, 1H), 7.15 (t, J=7.4 Hz, 1H), 7.02 (m, 1H), 6.95 (m,2H), 6.89 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.85 (s, 1H), 6.77 (dd, J=0.8Hz, J=7.8 Hz, 1H), 4.91 (m, 1H) , 4.84 (m, 1H), 4.21 (m, 1H), 3.98 (t,J=5.1 Hz, 2H), 3.67 (m, 2H), 3.44 (m, 1H), 3.24 (m, 2H), 3.05 (m, 1H),2.22 (s, 3H), 1.80 (m, 2H), 1.58 (s, 3H).

[1783] MS m/z 486 [M−1].

Example 3425-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid

[1784]

[1785]¹H NMR (400 MHz, DMSO-d₆) δ 13.57 (s, NH, 1H), 12.05 (s, 1H),11.05 (s, NH, 1H), 7.55 (m, 2H), 7.38 (m, 2H), 7.15 (t, J=7.8 Hz, 1H),6.88 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.73 (dd, J=0.8 Hz, J 7.4 Hz, 1H),6.65 (s, 1H), 2.42 (s, 3H), 1.75 (s, 3H).

[1786] MS m/z 391 [M−1].

Example 3432-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid

[1787]

[1788] MS m/z 377 [M−1].

Example 3443-[1-[3,5-Dimethyl-4-(4-morpholin-4-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluorophenyl)-1,3-dihydro-indol-2-one

[1789]

[1790] To a stirred mixture of 4-amino-1-benzylpiperidine (1.53 mL, 7.5mmol), K₂CO₃ (2.28g, 16.5 mmol) and DMF (15 mL) heated at 50° C. wasadded dropwise over 60 min bis(2-bromoethyl) ether (0.96 mL, 7.65 mmol).After stirring for 6 hours at 80° C., the solvent was removed by blowingwith a stream of nitrogen over 2 hours. The residue was purified on asilica gel column to give 1.7 g (87%) of4-(1-benzyl-piperidin-4-yl)-morpholine as a waxy solid.

[1791]¹H NMR (400 MHz, DMSO-d₆) δ 7.31 (m, 4H), 7.26 (m, 1H), 3.72 (t,4H), 3.49 (s, 2H), 2.94 (br d, 2H), 2.54 (t, 4H), 2.19 (tt, 1H), 1.96(td, 2H), 1.78 (br d, 2H), 1.55 (m, 2H).

[1792] 4-(1-benzyl-piperidin-4-yl)-morpholine (1.56 g, 6.0 mmol) washydrogenated using Pd(OH)₂ (20% on carbon, 390 mg, 25 wt%), 1.7 M HCl(10.6 mL) in methanol (50 mL) at 50° C. for 10 hours. The resulted aminedihydrochloride off-white solid was subjected to free-basing usingexcess basic resin to give 932 mg (91%) of 4-piperidin-4-yl-morpholineas waxy crystalline solid.

[1793]¹H NMR (400 MHz, DMSO-d₆) δ 3.53 (br s, 4H), 3.30 (v br s, 1H),2.92 (br d, 1H), 2.41 (s, 4H), 2.35 (m, 2H), 2.12 (br t, 1H), 1.65 (brd, 2H), 1.18 (br q, 2H).

[1794] MS m/z 171 [M⁺+1].

[1795]5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (1 eq.) and BOP (1.25 eq.) were suspended in DMF (5 mL) at rt andTEA (2.4 eq.) was added. After 15 mina, to the homogenous reactionmixture was added 4-piperidin-4-yl-morpholine (1.25 eq.) all at once.After stirring for 2 days, the reaction was added to a mixture ofchloroform-isopropanol (5:1) and 5% aq. LiC1. The organic layer wasseparated, washed with 5% aq. LiCl (2×), 1 M aq. NaOH (3×), brine, driedand concentrated. The residue was purified to give the titled compound

[1796]¹H NMR (400 MHz, DMSO-d6) δ 13.42 (s, 1H, NH), 11.04 (s, 1H, NH),7.57 (q, J=7.4 Hz, 1H), 7.29 (m, 3H), 7.18 (t, J=7.6 Hz, 1H), 6.93 (d,J=7.8 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 6.75 (s, 1H), 3.53 (m, 5H), 2.85(m, 2H), 2.41 (m, 5H), 2.31 (m, 1H), 2.22 (m, 4H), 1.75 (m, 2H), 1.57(m, 4H).

[1797] MS m/z 529.2 [M⁺+1].

Example 345 4-(3,4-Dimethoxy-phenyl)-3-[1-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1798]

[1799]¹H NMR (400 MHz, DMSO-d₆) δ 13.47 (s, NH, 1H), 11.06 (s, NH, 1H),7.3 5 (d, J =3. 1 Hz, 1H), 7.17 (t, J =7.8 Hz, 1H), 7. 10 (d, J =8.2 Hz,1H), 6.99 (d, J=2.0 Hz, 1H), 6.92 (m, 2H), 6.8 8 (d, J=7.0 Hz, 1H), 6.81(d, J=7.8 Hz, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.43 (m, 4H), 2.25 (m,4H), 2.15 (s, 3H), 1.64 (s, 3H).

[1800] MS m/z 485 [M−1].

Example 3464-(3,4-Dimethoxy-phenyl)-3-[1-[3-((cis)-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1801]

[1802]¹H NMR (400 MHz, DMSO-d₆) δ 13.61 (s, NH, 1H), 11.06 (s, NH, 1H),7.14 (m, 2H), 6.98 (m, 1H), 6.87 (m, 3H), 6.73 (dd, J=0.8 Hz, J =7.4 Hz,1H), 6.03 (s, 1H), 4.05 (m, 1H), 3.82 (s, 3H), 3.65 (s, 3H), 3.32 (m,1H), 2.41 (m, 2H), 2.31 (s, 3H), 2.19 (m, 2H), 1.92 (br m, 1H), 0.99 (m,3H), 0.79 (m, 3H) .

[1803] MS m/z 499 [M−1].

Example 3475-[4-(3,4-Dimethoxy-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1804]

[1805]¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, NH, 1H), 10.98 (s, NH, 1H),7.42 (t, 1H), 7.14 (t, 1H), 7.11 (d, 1H), 6.98 (d, 1H), 6.91 (m, 2H),6.86 (s, 1H), 6.79 (dd, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.28 (m, 4H),2.45 (m, 4H), 2.35 (s, 3H), 1.71 (s, 3H), 1.64 (m, 4H) .

[1806] MS m/z 513 [M−1].

Example 3482-[4-(3,4-Dimethoxy-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1807]

[1808]¹H NMR (400 MHz, DMSO-d₆) o 13.87 (s, NH, 1H), 11.06 (s, NH, 1H),8.10 (s, 1H), 7.85 (m, 1H), 7.6 (m, 1H), 7.15 (t, J=7.4 Hz, 1H), 6.99(d, J=7.8 Hz, 1H), 6.89 (s, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.77 (d, J=7.8Hz, 1H), 6.33 (s, 1H), 3.81 (s, 3H), 3.61 (s, 3H), 3.05 (m, 2H), 2.54(m, 2H), 2.28 (s, 3H), 1.72 (m, 6H), 1.60 (m, 1H), 1.24 (m, 2H), 0.82(m, 1H) .

[1809] MS m/z 513 [M−1].

Example 3494-(3,4-Dimethoxy-phenyl)-3-[1-[5-methyl-3-(4-pyrrolidin-1l-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1810]

[1811]¹H NMR (400MHz, DMSO-d₆) δ 13.61 (s, NH, 1H), 11.06 (s, NH, 1H),7.14 (t, J=7.8 Hz, 1H), 7.10 (br s, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.87(m, 3H), 6.73 (dd, J=0.8 Hz, J=7.8 Hz, 1H), 6.04 (d, J=2.0 Hz, 1H), 3.99(m, 1H), 3.81 (s, 3H), 3.68 (s, 3H), 3.43 (m, 1H), 2.68 (m, 2H), 2.44(m, 4H), 2.30 (s, 3H), 2.09 (m, 1H), 1.74 (m, 2H), 1.65 (m, 5H), 1.17(m, 1H) .

[1812] MS m/z 539 [M-l].

Example 350 4-(3,4-Dimethoxy-phenyl)-3-[[-4-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1813]

[1814]¹H NMR (400 MHz, DMSO-d₆) δ 13.37 (s, NH, 1H), 10.97 (s, NH, 1H),7.14 (t, J=7.8 Hz, 1H), 7.09 (d, J=8.2 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H),6.91 (dd, J=2.0 Hz, J=7.8 Hz, 1H), 6.88 (d, J =6.6 Hz, 1H), 6.94 (s,1H), 6.79 (d, J =6.6 Hz, 1H), 4.90 (m, 1H), 4.21 (m, 1H), 3.79 (s, 3H),3.71 (s, 3H), 3.48 (m, 2H), 3.25 (m, 2H), 2.21 (s, 3H), 1.81 (m, 2H),1.59 (s, 3H).

[1815] MS m/z 486 [M−1].

Example 3512,4-Dimethyl-5-[4-(3-methylcarbamoyl-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

[1816]

[1817]¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (s, NH, 1H), 11.06 (s, NH, 1H),8.52 (m, 1H), 7.95 (m, 1H), 7.90 (s, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.56(m, 1H), 7.43 (t, J=5.5 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 6.93 (dd, J=0.8Hz, J=7.8 Hz, 1H), 6.80 (dd, J=0.8 Hz, J=7.4 Hz, 1H), 6.72 (s, 1H), 3.24(m, 2H), 2.75 (d, J=4.7 Hz, 3H), 2.42 (m, 4H), 2.35 (s, 3H), 1.64 (m,4H), 1.58 (s, 3H).

[1818] MS m/z 510[M−1].

Example 3525-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid 12-(1,1-dioxo-1λ-thiomorpholin-4-yl)-ethyl]-amide

[1819]

[1820]¹H NMR (400 MHz, DMSO-d₆) δ 13.39 (s, NH, 1H), 10.99 (s, NH, 1H),7.55 (m, 2H), 7.38 (m, 3H), 7.13 (t, J=7.8 Hz, 1H), 6.88 (dd, J=0.8 Hz,J=7.8 Hz, 1H), 6.74 (dd, J=1.2 Hz, J=7.8 Hz, 1H), 6.60 (s, 1H), 3.22 (m,2H), 3.00 (m, 4H), 2.87 (m, 4H), 2.54 (t, J=6.3 Hz, 2H), 2.32 (s, 3H),1.68 (s, 3H) .

[1821] MS m/z 552 [M−1].

Example 3535-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid [2-(1,1-dioxo-1λ-thiomorpholin-4-yl)-ethyl]-amide

[1822]

[1823]¹H NMR (400 MHz, DMSO-d₆) δ 13.48 (s, NH, 1H), 11.13 (s, NH, 1H),7.76 (m, 1H), 7.68 (d, J=3.1 Hz, 1H), 7.58 (m, 1H), 7.43 (m, 3H), 7.23(t, J=7.8 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 6.83 (d, J=7.4 Hz, 1H), 6.72(s, 1H), 3.24 (m, 2H), 3.04 (m, 4H), 2.91 (m, 4H), 2.57 (t, J=6.6 Hz,2H), 1.78 (s, 3H) .

[1824] MS m/z 551 [M−1].

Example 3545-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid [2-(1,1-dioxo-1-thiomorpholin-4-yl)-ethyl]-amide

[1825]

[1826]¹H NMR (400 MHz, DMSO-d₆) δ 13.48 (s, NH, 1H), 11.18 (s, NH, 1H),7.79 (t, 1H), 7.70 (d, 1H), 7.65 (m, 1H), 7.35 (m, 2H), 7.26 (t, 1H),6.99 (d, 1H), 6.89 (d, 1H), 6.67 (s, 1H), 3.25 (m, 2H), 3.04 (m, 4H),2.91 (m, 4H), 2.58 (t, 2H), 1.82 (s, 3H).

[1827] MS m/z 539 [M−1].

Example 3555-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid 12-(1,1-dioxo-1λ-thiomorpholin-4-yl)-ethyl]-amide

[1828]

[1829]¹H NMR (400 MHz, DMSO-d₆) δ 13.54 (s, NH, 1H), 11.00 (br s, NH,1H), 7.63 (m, 1H), 7.47 (t, J=5.5 Hz, 1H), 7.33 (m, 2H), 7.22 (t, J=7.8Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.39 (s, 1H),3.27 (m, 2H), 3.05 (m, 4H), 2.91 (m, 4H), 2.58 (t, J=6.3 Hz, 2H), 2.38(s, 3H), 1.71 (s, 3H) .

[1830] MS m/z 553 [M−1].

Example 3562-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid 12-(1,1-dioxo-1λ-thiomorpholin-4-yl)-ethyl]-amide

[1831]

[1832]¹H NMR (400 MHz, DMSO-d₆) δ 13.80 (s, NH, 1H), 11.19 (s, NH, 1H),7.91 (m, 1H), 7.81 (m, 1H), 7.51 (m, 1H), 7.20 (m, 3H), 6.98 (m, 1H),6.82 (m, 1H), 6.40 (m, 1H), 3.18 (m, 2H), 3.12 (m, 4H), 2.95 (m, 4H),2.55 (m, 2H), 2.31 (s, 3H).

[1833] MS m/z 539 [M−1].

Example 3575-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid

[1834]

[1835]¹H NMR (400 MHz, DMSO-d₆) δ 13.69 (s, NH, 1H), 12.12 (s, 1H),11.18 (s, NH, 1H), 7.64 (m, 1H), 7.34 (m, 2H), 7.24 (t, J=7.8 Hz, 1H),7.00 (d, J=7.8 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.64 (s, 1H), 3.32 (s,3H), 1.79 (s, 3H) .

[1836] MS m/z 393 [M−1].

Example 3582-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid

[1837]

[1838]¹H NMR (400 MHz, DMSO-d₆) 612.10 (s, 1H), 11.13 (s, NH, 1H), 7.83(s, 1H), 7.51 (m, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.19 (m, 2H), 7.00 (dd,J=0.8 Hz, J=7.4 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.40 (d, J=2.3 Hz, 1H),2.30 (s, 3H).

[1839] MS m/z 379 [M−1].

Example 3595-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid

[1840]

[1841]¹H NMR (400 MHz, DMSO-d₆) δ 13.58 (s, NH, 1H), 11.22 (s, NH, 1H),7.75 (d, J=3.1 Hz, 1H), 7.64 (m, 1H), 7.34 (m, 2H), 7.27 (t, J=7.8 Hz,1H), 7.00 (d, J =7.0 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.66 (s, 1H), 1.82(s, 3H).

[1842] MS m/z 379 [M−1].

Example 360 3-[ 1 (4{(S)2-1(Cyclopropylrnethyl-amino)-methyl[-pyrrolidine1-carbonyl}-3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene[-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1843]

[1844] To a solution of5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (70 mg, 0.185 mmol), EDC (70 mg, 0.37 mmol), HOBt (26 mg, 0.19mmol) in DMF (4 mL) was added TEA (0.08 mL) andcyclopropylmetyl]-(dS)-1-pyrrolidin-2-ylmethyl-amine (0.05 mL, 0.37mmol). The mixture was stirred at rt for 20 hours. The reaction wasdiluted with DCM, washed with water, NaHCO₃, dried and concentrated. Theresidue was purified on a silica gel column to give the titled compound.

[1845]¹H NMR (400 MHz, CD₂Cl₂) δ 12.9 (br s, 1H, NH), 8.6 (br s, 1H),7.06 (m, 1H), 6.8 9m, 4H), 6.6 (m, 1H), 6.45 (m, 2H), 4.07 (m, 1H), 2.9(m, 3H), 2.6 (m, 2H), 2.4 (m, 1H), 2.0 (m, 1H), 1.92 (s, 3H, CH₃), 1.3(m, 2H), 1.26 (s, 3H, CH₃), 0.84 (m, 2H), 0.3 (m, 2H), 0.08 (m, 2H).

[1846] MS m/z 513.6 [M⁺+1].

Example 3613-[1-(3-{(S)-2-[(Cyclopropylmethyl-amino)-methyl]-pyrrolidine-1-carbonyl}-5-methyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1847]

[1848] To a solution of2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (80 mg, 0.22 mmol), EDC (80 mg), HOBt (30 mg) in DMF (4 mL) wasadded TEA (0.08 mL) andcyclopropylmethyl-(S)-1-pyrrolidin-2-ylmethyl-amine (0.05 mL). Themixture was stirred at rt for 20 hours. The reaction was diluted withDCM, washed with water, NaHCO₃, dried and concentrated. The residue waspurified on a silica gel column to give the titled compound.

[1849] MS m/z 499.6 [M⁺+1].

Example 3624-(2,6-Difluoro-phenyl)-3-[1-[4-((S)-pyrrolidine-2-carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepin-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1850]

[1851](S)-2-(2-Formyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.2 mmol) was condensed with4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one (0.2 mmol) andpiperidine (2 drops) in ethanol (2 mL) to give 20 mg of the titledcompound as a yellow solid.

[1852]¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (br s, 1H, NH), 11.16 (s, 1H,NH), 7.62 (m, 1H), 7.27 (m, 4H), 6.99 (d, 1H), 6.88 (d, 1H), 6.37 (s,1H), 6.19 (s, 1H), 4.52 (s, 1H), 3.55 (m, 2H), 3.37 (m, 2H), 2.88 (m,1H), 2.70 (m, 1H), 1.90 (m, 2H), 1.62-1.76 (m, 6H).

[1853] MS m/z 487.4 [M−1].

Example 3632-[4-(3,5-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide

[1854]

[1855] 4-(3,5-Difluoro-phenyl)-1,3-dihydro-indol-2-one (73.5 mg, 0.3mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid(2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide (excess) and piperidine inethanol to give 40 mg of the titled compound as a yellow solid.

[1856]¹H NMR (400 MHz, DMSO-d₆) δ 13.87 (s, NH, 1H), 11.20 (s, 1H, NH),8.10 (m, s, 2H), 7.29 (m, 1H), 7.21 (t, 1H), 7.05 (m, 2H), 6.94 (dd,1H), 6.78 (dd, 1H), 6.54 (d, 1H), 5.83 (d, 1H), 3.94 (m, 1H), 3.75 (m,2H), 3.15 (m, 3H), 3.05 (m, 4H), 2.31 (s, 3H, CH₃), 1.98 (m, 2H), 1.88(m, 2H).

[1857] MS m/z 507.2 [M⁺+1].

Example 3642-[4-(2,4-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide

[1858]

4-(2,4-Difluoro-phenyl)-1,3-dihydro-indol-2-one (73.5 mg, 0.3 mmol) wascondensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid(2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide (excess) and piperidine inethanol to give 75 mg (60%) of the titled compound as a yellow solid.

[1859]¹H NMR (400 MHz, DMSO-d₆) δ 13.86 (br s, NH, 1H), 11.17 (s, 1H,NH), 7.95 (m, 1H), 7.91 (m, 1H), 7.38 (m, 1H), 7.21 (m, 1H), 7.15 (m, t,2H), 6.95 (dd, 1H), 6.77 (dd, 1H), 6.46 (m, 1H), 3.77 (m, 1H), 3.25 (m,2H), 3.03 (m, 1H), 2.6-2.9 (m, 5H), 2.3 (s, 3H, CH₃), 1.79 (m, 4H).

[1860] MS m/z 507.4 [M⁺+1].

Example 3652-[4-(3-Chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide

[1861]

[1862] 4-(3-Chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (78.3 mg,0.3 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide (excess) and piperidinein ethanol to give 75 mg (60%) of the titled compound as a yellow solid.

[1863]¹H NMR (400 MHz, DMSO-d₆) δ 13.82 (s, NH, 1H), 11.16 (s, 1H, NH),7.99 (s, 1H), 7.96 (m, 1H), 7.51 (dd, 1H), 7.42 (t, 1H), 7.31 (m, 1H),7.20 (t, 1H), 6.93 (d, 1H), 6.78 (d, 1H), 6.47 (d, 1H), 3.82 (m, 1H),3.27 (m, 2H), 2.7-3.05 (m, 6H), 2.30 (s, 3H, CH₃), 1.83 (m, 4H).

[1864] MS m/z 523.4 [M⁺+1].

Example 3662-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide

[1865]

[1866] Yellow solid.

[1867]¹H NMR (400 MHz, DMSO-d₆) δ 13.80 (br s, NTH, 1H), 11.10 (s, 1H,NH), 7.93 (s, 1H), 7.86 (m, 1H), 7.39 (d, 2H), 7.29 (d, 2H), 7.14 (t,1H), 6.86 (d, 1H), 6.70 (d, 1H), 6.40 (d, 1H), 3.78 (m, 1H), 3.22 (m,3H), 3.02 (m, 1H), 2.7-2.9 (m, 4H), 2.25 (s, 3H, CH₃), 1.79 (m, 4H).

[1868] MS m/z 505.4 [M⁺+1].

Example 3672-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-methyl-amide

[1869]

2-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (115 mg, 0.3 mmol) was coupled with1-methylamino-3-pyrrolidin-1-yl-propan-2-ol (3 eq.), EDC (2 eq.), HOBt(1 eq.) in DMF ( 1.5 mL) to give 108 mg of the titled compound as ayellow solid.

[1870] MS 521.2 [M⁺+1].

Example 3684-(3-Fluoro-phenyl)-3-[1-[4-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1871]

[1872]¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (s, NH, 1H), 10.92 (s, NH, 1H),7.57 (m, 1H), 7.29 (m, 3H), 7.14 (t, 1H), 6.91 (d, 1H), 6.76 (m, 2H),4.17 (m, 1H), 2.45 (m, 2H), 2.29 (s, 3H), 2.21 (m, 2H), 1.95 (m, 1H),1.62 (s, 3H), 1.58 (m, 2H), 1.28 (m, 1H), 0.82 (m, 1H).

[1873] MS m/z 430 [M--1]

Example 3694-(2-Fluoro-phenyl)-3-[1-[4-(3-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1874]

[1875]¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (s, NH, 1H), 10.90 (s, NH, 1H),7.49 (m, 1H), 7.35 (m, 3H), 7.11 (t, J=7.8 Hz, 1H), 6.88 (d, J=7.8 Hz,1H), 6.74 (d, J=8.2 Hz, 1H), 6.56 (s, 1H), 4.45 (m, 1H), 3.10 (m, 2H),2.19 (s, 3H), 2.11 (m, 2H), 1.68 (m, 2H), 1.50 (s, 3H), 1.41 (m, 2H),1.25 (m, 2H), 0.95 (m, 1H).

[1876] MS m/z 444 [M−1].

Example 3702-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-piperidin-1-yl-ethyl)-amide

[1877]

[1878]2-4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (90.5 mg) was coupled with 2-piperidin-1-yl-ethylamine (48 mg, 1.5eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL), DMF(0.3 mL) at rt for overnight to give 82 mg (70%) of the titled compoundas a yellow solid.

[1879]¹H NMR (400 MHz, DMSO-d₆) o 13.80 (br s, NH, 1H), 11.12 (s, 1H,NH), 7.99 (s, 1H), 7.70 (t, 1H), 7.45 (m, 1H), 7.17 (m, 4H), 6.91 (dd,1H), 6.76 (dd, 1H), 6.35 (d, 1H), 3.13 (m, 2H), 2.37 (m, 4H), 2.29 (m,s, 5H), 1.50 (m, 4H), 1.39 (m, 2H).

[1880] MS m/z 473.6 [M⁺+1].

Example 3712-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid [2-(3-acetylamino-pyrrolidin-1-yl)-ethyl]-amide

[1881]

[1882]2-4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (90.5 mg) was coupled withN-[1-(2-amino-ethyl)-pyrrolidin-3-yl]-acetamide (58.5 mg, 1.5 eq.), HOBt(1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL), DMF (0.3 mL) atrt for overnight to give 97 mg (78%) of the titled compound as a yellowsolid.

[1883]¹H NMR (400 MHz, DMSO-d₆) o 13.80 (s, NH, 1H), 11.12 (s, 1H, NH),7.99 (s, 1H), 7.98 (m, 1H), 7.77 (t, 1H), 7.45 (m, 1H), 7.17 (m, 4H),6.91 (dd, 1H), 6.74 (dd, 1H), 6.35 (d, 1H), 4.14 (m, 1H), 3.12 (m, 2H),2.6-2.72 (m, 2H), 2.42 (m, 3H), 2.33 (m, 1H), 2.29 (s, 3H, CH₃), 2.05(m, 1H), 1.76 (s, 1H, CH₃), 1.53 (m, 1H).

[1884] MS m/z 516.4 [M++I].

Example 3722-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-zarboxylicacid (1-methyl-piperidin-4-ylmethyl)-amide

[1885]

[1886]2-4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (90.5 mg) was coupled with C-(1-methyl-piperidin-4-yl)-methylamine(1.5 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL),DMF (0.3 mL) at rt for overnight to give 65 mg (55%) of the titledcompound as a yellow solid.

[1887]¹H NMR (400 MHz, DMSO-d₆) δ 13.80 (br s, NH, 1H), 11.11 (s, 1H,NH), 8.00 (s, 1H), 7.81 (t, 1H), 7.42 (m, 1H), 7.16 (m, 4H), 6.91 (dd,1H), 6.75 (dd, 1H), 6.39 (d, 1H), 2.90 (t, 2H), 2.72 (m, 2H), 2.29 (s,3H, CH₃), 2.13 (s, 3H, CH₃), 1.79 (m, 2H), 1.54 (m, 2H), 1.38 (m, 1H),1.12 (m, 2H).

[1888] MS m/z 473.6[M⁺+1].

Example 3732-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid 12-(4-hydroxy-piperidin-1-yl)-ethyl]-amide

[1889]

[1890]2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (90.5 mg) was coupled with 1-(2-amino-ethyl)-piperidin-4-ol (54 mg,1.5 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL),DMF (0.3 mL) at rt for overnight to give 69.8 mg (57%) of the titledcompound as a yellow solid.

[1891]¹H NMR (400 MHz, DMSO-d₆) o 13.80 (br s, NH, 1H), 11.12 (s, 1H,NH), 7.99 (s, 1H), 7.71 (t, 1H), 7.43 (m, 1H), 6.91 (d, 1H), 6.76 (d,1H), 6.35 (d, 1H), 4.53 (d, 1H), 3.43 (m, 1H), 3.12 (m, 2H), 2.71 (m,2H), 2.30 (m, 2H), 2.29 (s, 3H, CH₃), 2.05 (m, 2H), 1.69 (m, 2H), 1.38(m, 2H).

[1892] MS m/z 489.4 [M⁺+1].

Example 3742-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid 13-(1,1-dioxo-1$1%6&-thiomorpholin-4-yl)-2-hydroxy-propyl]-amide

[1893]

2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (108 mg, 0.3 mmol) was coupled with1-amino-3-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-propan-2-ol (1.8 mmol),HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (1 mL),acetonitrile (1 mL) at rt for overnight to give 107 mg (65%) of thetitled compound as a yellow solid.

[1894]¹H NMR (400 MHz, DMSO-d₆) δ 13.84 (br s, NH, 1H), 11.13 (s, 1H,NH), 8.00 (s, 1H), 7.79 (t, 1H), 7.44 (m, 1H), 7.17 (m, 4H), 6.91 (dd,1H), 6.76 (dd, 1H), 6.42 (d, 1H), 4.76 (d, 1H), 3.67 (m, 1H), 3.17 (m,1H), 3.06 (m, 4H), 2.96 (m, 6H), 2.29 (s, 3H, CH₃).

[1895] MS m/z 551.2 [M−1].

Example 3755-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid 13-(1,1-dioxo-1l6-thiomorpholin-4-yl)-2-hydroxy-propyl]-amide

[1896]

[1897]5-4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (112 mg, 0.3 mmol) was coupled with 1-amino-3-(1,1-dioxo-1k6-thiomorpholin-4-yl)-propan-2-ol (1.8 mmol), HOBt (1 eq.), EDC (1.5eq.) and TEA (3 drops) in THF (1 mL), acetonitrile (1 mL) at rt forovernight to give 96.2 mg (55%) of the titled compound.

[1898]¹H NMR (400 MHz, DMSO-d₆) δ 13.49 (s, NH, 1H), 11.10 (br s, 1H,NH), 7.59 (d, 1H), 7.44 (m, 1H), 7.17 (t, 1H), 6.91 (d, 1H), 6.77 (d,1H), 6.65 (s, 1H), 4.8 (m, 1H), 3.71 (m, 1H), 3.35 (m, 1H), 3.12 (m,1H), 3.05 (m, 4H), 2.94 (m, 4H), 2.5 (m, 1H), 2.43 (m, 1H), 2.37 (s, 3H,CH₃), 1.72 (s, 3H, CH₃).

[1899] MS m/z 581.2 [M−1].

Example 3765-[4-(2,6-Difluoro-phenyl)-2-oxo1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid [3-(1,1-dioxo-1l6-thiomorpholin4-yl)-2-hydroxy-propyl]-amide

[1900]

[1901]5-4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (114 mg, 0.3 mmol) was coupled with1-amino-3-(1,1-dioxo-[6-thiomorpholin-4-yl)-propan-2-ol (1.8 mmol), HOBt(1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (1 mL), acetonitrile (1mL) at rt for overnight to give 102 mg (60%) of the titled compound.

[1902]¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (s, NH, 1H), 11.20 (br s, 1H,NH), 7.81 (d, 1H), 7.74 (d, 1H), 7.65 (m, 1H), 7.34 (m, 2H), 7.25 (t,1H), 6.99 (dd, 1H), 6.88 (d, 1H), 6.66 (s, 1H), 4.83 (d, 1H), 6.66 (s,1H), 4.83 (m, 1H), 3.70 (m, 1H), 3.35 (m, 1H), 3.08 (m, 1H), 3.04 (m,4H), 2.93 (m, 4H), 2.50 (m, 1H), 2.40 (m, 1H), 1.81 (s, 3H, CH₃).

[1903] MS m/z 569.2 [M−1].

Example 3774-(2,6-Difluoro-phenyl)-3-[1-[3-methyl-4-((S)-3-pyrrolidin-1-ylmethyl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1904]

[1905]5-4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (114 mg, 0.3 mmol) was coupled with(R)-3-pyrrolidin-1-ylmethyl-piperidine (99 mg, 2 eq.), HOBt (1 eq.), EDC(1.5 eq.) and TEA (3 drops) in THF (1 mL) and aceonitrile (1 mL) at rtfor overnight to give 111.3 mg (70%) of the titled compound as a yellowsolid.

[1906] MS m/z 531 [M⁺+1].

Example 3784-(4-Chloro-phenyl)-3-[1-[3,5-dimethyl-4-((S)-3-pyrrolidin-1-ylmethyl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1907]

[1908]5-4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (112 mg, 0.3 mmol) was coupled with(R)-3-pyrrolidin-1-ylmethyl-piperidine (99 mg, 2 eq.), HOBt (1 eq.), EDC(1.5 eq.) and TEA (3 drops) in THF (1 mL) and acetonitrile (1 mL) at rtfor overnight to give 89.5 mg (55%) of the titled compound as a yellowsolid.

[1909] MS m/z 543 [M⁺+1].

Example 3794-(3-Fluorophenyl)-3-[1-[5-methyl-3-(4-pyrrolidin-1-ylmethyl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1910]

[1911]2-4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (108 mg, 0.3 mmol) was coupled with(R)-3-pyrrolidin-1-ylmethyl-piperidine (99 mg, 2 eq.), HOBt (1 eq.), EDC(1.5 eq.) and TEA (3 drops) in THF (1 mL), acetonitrile (1 mL) at rt forovernight to give 107 mg (70%) of the titled compound as a yellow solid.

[1912] MS 513.2 [M⁺+1].

Example 380 3-[1-[3,5-Dimethyl-4-(l-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1913]

[1914]¹H NMR (400 MHz, DMSO-d₆) δ 13.4 (s, 1H, NH), 10.95 (s, 1H, NH),7.56 (m, 1H), 7.28 (m, 3H), 7.14 (t, 1H), 6.91 (dd, 1H), 6.77 (dd, 1H),6.76 (s, 1H), 5.40 (m, 1H), 2.95 (m, 2H), 2.50 (m, 2H), 2.25 (s, 3H,CH₃), 2.21 (s, 3H, CH₃), 2.17 (m, 2H), 1.55 (s, 3H, CH₃).

[1915] MS m/z 428.2 [M⁺+1].

Example 3812-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid [2-(2,2,2-trifluoro-ethylamino)-ethyl]-amide

[1916]

[1917] A mixture of2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (53 mg, 0.15 mmol), HOBt (28 mg), EDC (36 mg), TEA (0.042 mL) andN¹-(2,2,2-trifluoro-ethyl)-ethane-1,2-diamine (0.036 mL) in DMF (1 mL)was stirred at rt for 48 hours. The solvent was removed and diluted withsat. NaHCO₃. It was then extracted with DCM, dried and concentrated. Theresidue was purified on a silica gel column to give 52 mg (71%) of thetitled compound.

[1918]¹H NMR (400 MHz, DMSO-d₆) δ 13.8 (s, 1H, NH), 11.14 (s, 1H, NH),7.98 (s, 1H), 7.8 (t, 1H), 7.45 (m, 1H), 7.19 (m, 4H), 6.93 (d, 1H),6.78 (d, 1H), 6.38 (d, 1H), 3.26 (m, 2H), 3.12 (m, 2H), 2.67 (t, 2H),2.31 (s, 3H, CH₃).

[1919] MS m/z 487.4 [M⁺+1].

Example 3823-[1-[4-(1-Acetyl-piperidine-4-carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepin-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1920]

[1921]4-(1-Acetyl-piperidine-4-carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde(56 mg) was condensed with 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one(40 mg) and piperidine (2 drops) in ethanol (1 mL) at rt for overnight.The solvent was concentrated and the residue was purified on a silicagel column to give 50 mg of the title compound as a yellow solid.

[1922]¹H NMR (400 MHz, CD₂Cl₂) δ 13.47 (s, 1H, NH), 9.16 (br s, 1H, NH),7.48 (m, 1H), 7.2-7.3 (m, 4H), 6.97 (d, 1H), 6.88 (d, 1H), 6.76 (s, 1H),6.09 (s, 1H), 4.50 (d, 1H), 3.77 (d, 1H), 2.91 (m, 2H), 2.78 (m, 2H),2.4 (m, 1H), 2.04 (s, 3H, CH₃), 1.94 (m, 1H), 1.82 (m, 3H), 1.70 (m,3H), 1.57 (m, 3H).

[1923] MS m/z 527.4 [M⁺+1].

Example 383(R)-1-{2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carbonyl}-piperidine-3-carboxylicacid cyclopropylamide

[1924]

[1925]2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (108 mg, 0.3 mmol) was coupled with (R)-piperidine-3-carboxylicacid cyclopropylamide (69.3 mg, 1.5 eq.), HOBt (40.5 mg, 1 eq.), EDC (86mg, 1.5 eq.) and TEA (0.06 mL) in DMF (1 mL) to give 57 mg (37%) of thetitled compound.

[1926] MS m/z 513.4[M⁺+1].

Example 3844-(3-Fluoro-phenyl)-3-[1-[4-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1927]

[1928] MS m/z 443.4 [M−1].

Example 3852-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1929]

[1930]¹H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H, NH), 11.10 (s, 1H, NH),7.63 (m, 2H), 7.4 (m, 1H), 7.22 (s, 1H), 7.14 (m, 3H), 7.01 (d, 1H),6.86 (dd, 1H), 6.71 (dd, 1H), 2.97 (m, 2H), 1.98 (s, 3H, CH₃), 1.59 (m,4H), 1.50 (m, 2H), 1.2 (m, 3H), 0.78 (m, 3H).

[1931] MS m/z 473.1 [M⁺+1].

Example 3863-[1-[3,5-Dimethyl4-(1-methyl-piperidin4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1932]

[1933]¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (s, 1H, NH), 10.9 (s, 1H, NH),7.56 (m, 1H), 7.27 (m, 3H), 7.12 (m, 1H), 6.90 (dd, 1H), 6.75 (m, 2H),2.78 (m, 2H), 2.34 (m, 1H), 2.27 (s, 3H, CH₃), 2.14 (s, 3H, CH₃), 1.86(m, 2H), 1.74 (m, 2H), 1.59 (s, 3H, CH₃), 1.44 (m, 2H).

[1934] MS m/z 430.2 [M⁺+1].

Example 387 3-[1-[3,5-Dimethyl4-(1-methyl-piperidin4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1935]

[1936]¹H NMR (400 MHz, DMSO-d₆) δ 13.31 (s, 1H, NH), 10.89 (s, 1H, NH),7.43 (m, 1H), 7.35 (m, 1H), 7.11 (t, 1H), 6.89 (dd, 1H), 6.73 (dd, 1H),6.68 (s, 1H), 2.78 (m, 2H), 2.34 (m, 1H), 2.34 (m, 1H), 2.27 (s, 3H,CH₃), 2.13 (s, 3H, CH₃), 1.85 (m, 2H), 1.76 (m, 2H), 1.60 (s, 3H CH₃),1.43 (m, 2H).

[1937] MS m/z 428.6 [M−1].

Example 388 4-(2,3-Difluoro-phenyl)-3-[1-[3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1938]

[1939]¹H NMR (400 MHz, DMSO-d₆) δ 13.35 (s, 1H, NH), 10.96 (s, 1H, NH),7.58 (m, 1H), 7.39 (m, 1H), 7.28 (m, 1H), 7.16 (t, 1H), 6.95 (dd, 1H),6.81 (dd, 1H), 6.62 (s, 1H), 2.78 (m, 2H), 2.35 (m, 1H), 2.28 (s, 3H,CH₃), 2.14 (s, 3H, CH₃), 1.86 (m, 2H), 1.75 (m, 2H), 1.61 (s, 3H, CH₃),1.45 (m, 2H). 114341 MS m/z 446.6 [M−1].

Example 3894-(3,5-Difluoro-phenyl)-3-[1-[3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1940]

[1941]¹H NMR (400 MHz, DMSO-d₆) δ 13.35 (s, 1H, NH), 10.93 (s, 1H, NH),7.3 7 (m, 1H), 7.2 (m, 2H), 7.13 (t, 1H), 6.92 (dd, 1H), 6.79 (s, 1H),6.77 (dd, 1H), 2.78 (m, 2H), 2.36 (m, 1H), 2.28 (s, 3H, CH₃), 2.14 (s,3H, CH₃), 1.86 (m, 2H), 1.77 (m, 2H), 1.67 (s, 3H, CH₃), 1.45 (,2H).

[1942] MS m/z 446.5 [M−1].

Example 390 4-(2,6-Difluoro-phenyl)-3-[1-[3,5-dimethyl4-(1l-methyl-piperidin-4-yl)-1H-pyrro1-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1943]

[1944]¹H NMR (400 MHz, DMSO-d₆) δ 13.36 (s, 1H, NH), 10.96 (s, 1H, NH),7.61 (m, 1H), 7.32 (m, 2H), 7.17 (t, 1H), 6.96 (dd, 1H), 6.83 (dd, 1H),6.56 (s, 1H), 2.78 (m, 2H), 2.34 (m, 1H), 2.28 (s, 3H, CH₃), 2.14 (s,3H, CH₃), 1.86 (m, 2H), 1.75 (m, 2H), 1.58 (s, 3H, CH₃), 1.45 (m, 2H).

[1945] MS m/z 446.5 [M−1].

Example 3914-(3,4-Dimethoxy-phenyl)-3-[1-[3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1946]

[1947]¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, 1H, NH), 10.84 (s, 1H, NH),7.09 (m, 2H), 6.96 (d, 1H), 6.89 (dd, 1H), 6.86 (d, 1H), 6.84 (s, 1H),6.76 (d, 1H), 3.80 (s, 3H, CH₃), 3.71 (s, 3H, CH₃), 2.86 (m, 2H), 2.40(m, 1H), 2.27 (s, 3H, CH₃), 2.22 (m, 2H), 1.78 (m, 2H), 1.61 (s, 3H,CH₃), 1.47 (m, 2H).

[1948] MS m/z 472.4 [M⁺+1].

Example 3925-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid

[1949]

[1950]¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H, OH), 11.28 (s, 1H, NH),7.88 (m, 1H), 7.44 (m, 1H), 7.i8-7.32 (m, 3H), 6.98 (dd, 1H), 6.80 (dd,1H), 6.40 (d, 1H), 2.30 (s, 3H, CH₃).

[1951] MS m/z 379.4 [M−1].

Example 3934-(2,4-Difluoro-phenyl)-3-[1-[3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1952]

[1953]¹H NMR (400 MHz, DMSO-d₆) δ 13.67 (s, 1H, NH), 12.12 (br s, 1H,COOH), 11.17 (s, 1H, NH), 7.61 (m, 1H), 7.41 (m, 1H), 7.30 (m, 1H), 7.24(t, 1H), 6.99 (dd, 1H), 6.87 (dd, 1H), 6.70 (s, 1H), 1.82 (s, 3H, CH₃).

[1954] MS M/z 393.2 [M−1].

Example 3944-(2,4-Difluoro-phenyl)-3-[1-[3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1955]

[1956]¹H NMR (400 MHz, DMSO-d₆) δ 13.33 (s, 1H, NH), 10.93 (s, 1H, NH),7.45 (m, 2H), 7.28 (m, 1H), 7.14 (t, 1H), 6.93 (dd, 1H), 6.77 (dd, 1H),6.56 (s, 1H), 2.79 (m, 2H), 2.35 (m, 1H), 2.28 (s, 3H, CH₃), 2.14 (s,3H, CH₃), 1.86 (m, 2H), 1.77 (m, 2H), 1.64 (s, 3H, CH₃), 1.45 (m, 2H).

[1957] MS m/z 448.1 [M⁺+1].

Example 3954-(2,3-Difluoro-phenyl)-3-[1-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1958]

[1959] Yellow solid.

[1960]¹H NMR (400 MHz, DMSO-d₆) δ 13.45 (s, 1H, NH), 11.12 (s, 1H, NH),7.6 (m, 1H), 7.41 (m, 1H), 7.29 (m, 1H), 7.22 (t, 1H), 6.98 (dd, 1H),6.85 (dd, 1H), 6.62 (d, 1H), 3.32 (m, 4H), 2.23 (s, m, 7H), 2.14 (s, 3H,CH₃), 1.59 (s, 3H, CH₃).

[1961] MS m/z 475.4 [M−1].

Example 3964-(2,3-Difluoro-phenyl)-3-[1-[3,5-dimethyl-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1962]

[1963] Yellow solid.

[1964]¹H NMR (400 MHz, DMSO-d₆) δ 13.43 (br s, 1H, NH), 11.11 (s, 1h,NH), 7.59 (m, 1H), 7.40 (m, 1H), 7.29 (m, 1H), 6.98 (dd, 1H), 6.85 (dd,1H), 6.62 (s, 1H), 3.32 (m, 2H), 2.94 (m, 2H), 2.43 (m, 4H), 2.22 (s,3H, CH₃), 2.14 (m, 1H), 1.77 (m, 2H), 1.63 (m, 4H), 1.58 (s, 3H), 1.22(m, 2H).

[1965] MS m/z 529.5 [M−1].

Example 3974-(2,3-Difluoro-phenyl)-3-[1-[3,5-dimethyl-4-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1966]

[1967] Yellow solid.

[1968]¹H NMR (400 MHz, DMSO-d₆) δ 13.4 (br s, 1H, NH), 11.10 (s, 1H,NH), 7.59 (m, 1H), 7.40 (m, 1H), 7.29 (m, 1H), 7.21 (t, 1H), 6.97 (dd,1H), 6.85 (dd, 1H), 6.61 (s, 1H), 4.22 (m, 1H), 3.12 (m, 2H), 2.45 (m,4H), 2.23 (s, 3H, CH₃), 2.1 (m, 2H), 1.85 (m, 4H), 1.65 (m, 2H), 1.6 (s,3H, CH₃), 1.45 (m, 2H).

[1969] MS m/z 529.5 [M−1].

Example 3984-(2,3-Difluoro-phenyl)-3-l1-[3-((cis)-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1970]

[1971] Orange solid.

[1972]¹H NMR (400 MHz, DMSO-d₆) δ 13.59 (s, 1H, NH), 11.16 (s, 1H, NH),7.44 (m, 1H), 7.14-7.3 (m, 3H), 6.97 (dd, 1H), 6.86 (s, 1H), 6.79 (dd,1H), 6.06 (d, 1H), 4.15 (m, 1H), 3.47 (m, 1H), 3.32 (m, under waterpeak), 2.45 (m, under DMSO peak), 2.31 (s, 3H, CH₃), 2.05 (m, 1H), 1.03(s, 3H, CH₃), 0.8 (s, 3H, CH₃).

[1973] MS m/z 475.4 [M−1].

Example 3992-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1974]

[1975] Orange solid.

[1976]¹H NMR (400 MHz, DMSO-d₆) δ 13.8 (s, 1H, NH), 11.2 (s, 1H, NH),7.9 (m, 2H), 7.28 (m, 1H), 7.26 (m, 1H), 7.22 (t, 1H), 7.14 (m, 1H),6.97 (dd, 1H), 6.79 (dd, 1H), 6.38 (d, 1H), 3.09 (m, 2H), 2.41 (m, 6H),2.3 (s, 3H, CH₃), 1.68 (m, 4H), 1.58 (m, 2H).

[1977] MS m/z 489.4 [M−1].

Example 4002-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-iodo-4-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

[1978]

[1979] Earthy yellow solid.

[1980]¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H, NH), 7.8 (t, 1H), 7.44(m, 1H), 7.2 (m, 4H), 7.1 (s, 1H), 6.93 (dd, 1H), 6.78 (dd, 1H), 3.02(m, 2H), 2.40 (m, 6H), 1.96 (s, 3H, CH₃), 1.63 (m, 4H), 1.52 (m, 2H).

[1981] MS m/z 597.3 [M−1].

Example 401 2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacidi(S)-2-hydroxy-3-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-propyl]-amide

[1982]

[1983] Orange solid.

[1984]¹H NMR (400 MHz, DMSO-d₆) o 13.84 (s, 1H, NH), 11.13 (s, 1H, NH),8.0 (s, 1H), 7.82 (t, 1H), 7.42 (m, 1H), 7.15 (m, 4H), 6.91 (d, 1H),6.76 (d, 1H), 6.42 (d, 1H), 4.98 (d, 1H), 3.96 (s, 2H), 3.76 (m, 2H),3.25 (m, 1H), 3.15 (m, 1H), 2.95 (m, 1H), 2.86 (s, 3H, CH₃), 2.3 (s, 3H,CH₃).

[1985] MS m/z 532.4 [M⁺+1].

Example 402 2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid[(R)-2-hydroxy-3-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-propyl]-amide

[1986]

[1987]¹H NMR (400 MHz, DMSO-d₆) δ 13.82 (s, 1H, NH), 11.13 (s, 1H, NH),8.0 (s, 1H), 7.83 (t, 1H), 7.42 (m, 1H), 7.15 (m, 4H), 6.91- (d, 1H),6.76 (d, 1H), 6.43 (d, 1H), 4.98 (d, 1H), 3.96 (s, 2H), 3.76 (m, 2H),3.25 (m, 1H), 3.15 (m, 1H), 2.95 (m, 1H), 2.86 (s, 3H, CH₃), 2.30 (s,3H, CH₃).

Example 4034-(3-Fluoro-phenyl)-3-l1-[5-methyl-3-(3-morpholin-4-yl-azetidine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1988]

[1989] Yellow solid.

[1990]¹H NMR (400 MHz, DMSO-d₆) δ 13.68 (s, 1H, NH), 11.14 (s, 1H, NH),7.51 (s, 1H), 7.48 (m, 1H), 7.2 (m, 4H), 6.92 (dd, 1H), 6.77 (dd, 1H),6.2 (d, 1H), 3.92 (m, 1H), 3.78 (m, 2H), 3.67 (m, 1H), 3.57 (m, 4H), 3.0(m, 1H), 2.29 (s, 3H, CH₃), 2.25 (m, 4H).

Example 4043-[1-{3-[3-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-azetidine-1-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[1991]

[1992] Yellow solid.

[1993]¹H NMR (400 MHz, DMSO-d₆) δ 13.78 (s, 1H, NH), 11.14 (s, 1H, NH),7.52 (s, 1H), 7.48 (m, 4H), 7.25 (m, 4H), 6.92 (dd, 1H), 6.77 (dd, 1H),6.2 (d, 1H), 3.8 (m, 1H), 3.78 (m, 2H), 3.67 (m, 1H), 3.55 (m, 2H), 2.96(m, 1H), 2.74 (m, 1H), 2.60 (m, 1H), 2.3 (s, 3H, CH₃), 1.45 (m, 2H),1.05 (d, 3H, CH₃), 0.99 (d, 3H, CH₃).

Example 405 4-(3-Fluoro-phenyl)-3-[1-{3-[(S)-2-((S)-3-fluoro-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1994]

[1995] To a solution of2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (100 mg, 0.28 mmol), EDC (115 mg, 0.3 mmol), HOBt (40 mg, 0.3 mmol)in DMF (4 mL) was added TEA (0.14 mL) and(S)-3-fluoro-1-(S)-1-pyrrolidin-2-ylmethyl-pyrrolidine (100 mg 0.58mmol). The mixture was stirred at rt for 20 hours. The reaction wasdiluted with DCM, washed with water, NaHCO₃, dried and concentrated. Theresidue was purified on a silica gel column to give the titled compound.

[1996] MS m/z 517.4 [M⁺+1].

Example 4064-(3-Fluoro-phenyl)-3-[1-{3-[(R)-2-((S)-3-fluoro-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[1997]

[1998] To a solution of2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (100 mg, 0.28 mmol), EDC (120 mg, 0.63 mmol), HOBt (40 mg, 0.3mmol) in DMF (4 mL) was added TEA (0.15 mL) and(S)-3-fluoro-1-(R)-1-pyrrolidin-2-ylmethyl-pyrrolidine (95 mg, 0.55mmol). The mixture was stirred at rt for 20 hours. The reaction wasdiluted with DCM, washed with water, NaHCO₃, dried and concentrated. Theresidue was purified on a silica gel column to give the titled compound.

[1999] MS m/z 517.4 [M⁺+1].

Example 407 3-[1-[3-(4-Cyclopropylamino-piperidine--carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[2000]

[2001] To a solution of2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (105 mg, 0.29mmol), EDC (120 mg, 0.58 mmol), HOBt (40 mg, 0.3 mmol) in DMF (4 mL) wasadded TEA 90.15 mL) and cyclopropyl-piperidin-4-yl-amine. The mixturewas stirred at rt for 20 hours. The reaction was diluted with DCM,washed with water, NaHCO₃, dried and concentrated. The residue waspurified on a silica gel column to give the titled compound.

[2002]¹H NMR (400 MHz, CDCl₃) δ 13.32 (s, 1H, NH), 8.35 (s, 1H), 7.46(m, 1H), 7.23 (m, 1H), 7.12 (m, 3H), 7.02 (br s, 1H, NH), 6.83 (dd, 1H),6.79 (dd, 1H), 5.99 (d, 1H), 4.44 (m, 1H), 3.66 (m, 1H), 2.81 (m, 1H),2.34 (s, 3H, CH₃), 2.15 (m, 1H) , 2.0 (m, 1H), 1.80 (m, 1H), 1.69 (m,2H), 1.28 (m, 1H), 1.1 (m, 1H), 0.47 (m, 2H), 0.34 (m, 2H).

[2003] MS m/z 485.2 [M⁺+1].

Example 4083-[1-[3-((2R,4R)-2-Cyclopropylaminomethyl-4-hydroxy-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[2004]

[2005] To a solution of cis-4-hydroxy-D-proline (6.5 g, 0.05 mol) in 10%TEA/MeOH (80 mL) was added di-tert-butyl dicarbonate (21.6 g, 2 eq.).After refluxing for 45 mins, the reaction was allowed to cool to rt andthe solvent was removed under reduced pressure. The residue was adjustedto pH 3-4 and extracted with ethyl acetate. The combined organic layerwas dried and concentrated to give 8 g of(2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl esteras a white semi-solid.

[2006]¹H NMR (400 MHz, DMSO-d₆) δ 4.13 (m, 1H), 4.01 (m, 1H), 3.41 (m,1H), 3.12 (m, 1H), 2.25 (m, 1H), 1.76 (m, 1H), 1.31 and 1.37 (2s, 9H,Boc).

[2007] Cyclopropylarnine was coupled with(2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester(8 g), EDC, HOBt, TEA in DMF to give 5 g of(2R,4R)-2-cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acidtert-butyl ester as a white semi-solid.

[2008]¹H NMR (400 MHz, DMSO-d₆) δ 4.06 (m, 1H), 3.97 (m, 1H), 3.42 (m,1H), 3.15 (m, 1H), 2.62 (m, 1H), 2.23 (m,l H), 1.64 (m, 1H), 1.33 (Boc),0.61 (m, 2H), 0.42 (m, 2H).

[2009] (2R,4R)-2-Cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylicacid tert-butyl ester (5 g) was deprotected using 50 mL of 30% TFA inDCM at rt for 2 hours to give 3g of(2R,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide as alight yellow oil.

[2010]¹H NMR (400 MHz, DMSO-d₆) δ 4.32 (m, 1H), 4.1 (m, 1H), 3.2 (m,2H), 2.67 (m, 1H), 2.35 (m, 1H), 1.85 (m, 1H), 0.67 (m, 2H), 0.45 (m,2H).

[2011] (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide(3 g) was reduced using LAH (2 g) in THF (150 mL) to give 1 g of(3R,5R)-5-cyclopropylaminomethyl-pyrrolidin-3-ol.

[2012] To a mixture of2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (100 mg, 0.28 mmol), EDC (64 mg, 1.2 eq.), HOBt (45 mg, 1.2 eq.) inDMF (3 mL) was added TEA (0.098 mL) and(3R,5R)-5-cyclopropylaminomethyl-pyrrolidin-3-ol. The mixture wasstirred at rt for overnight. After the usual work up, 65 mg of thetitled compound was obtained as a yellow solid.

[2013]¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H, NH), 7.46 (m, 1H), 7.19(m, 5H), 6.94 (d, 1H), 6.76 (d, 1H), 6.16 (s, 1H), 4.1 (m, 2H), 4.0 (m,1H), 3.48 (m, 1H), 3.16 (m, 1H), 2.80 (m, 1H), 2.55 (d, 1H), 2.33 (s,3H, CH₃), 2.15 (m, 2H), 1.72 (m, 1H), 0.34 (m, 2H), 0.2 (m, 2H).

[2014] MS m/z 501.4 [M⁺+1].

[2015] Example 409

2-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-cyclopropylamino-2-hydroxy-propyl)-amide

[2016]

[2017] Red solid.

[2018] MS m/z 491.3 [M−1].

Example 4102-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide

[2019]

[2020] Red solid.

[2021]¹H NMR (400 MHz, DMSO-d₆) δ 13.82 (s, 1H, NH), 11.20 (s, 1H, NH),8.0 (dd, 2H), 7.69 (m, 1H), 7.65 (m, 1H), 7.44 (m, 1H), 7.27 (m, 1H),7.23 (t, 1H), 7.14 (m, 1H), 6.98 (dd, 1H), 6.80 (dd, 1H), 6.47 (m, 1H),3.77 (m, 1H), 3.20 (m, 1H), 3.05 (m, 1H), 2.31 (s, 3H, CH₃), 1.82 (m,4H), 1.63 (m, 2H), 1.1 (m, 1H), 0.8 (m, 4H).

[2022] MS m/z 505.4 [M−1].

Example 4114-(2,3-Difluoro-phenyl)-3-[1-{3-[(S)-2-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[2023]

[2024] Yellow solid.

[2025] MS m/z 531.5 [M-l].

Example 4124-(2,3-Difluoro-phenyl)-3-[1-{3-[(S)-2-((S)-3-fluoro-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-yl}-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[2026]

[2027] Yellow solid.

[2028] MS m/z 533.5 [M−1].

Example 4133-[1-[3-((S)-3-Cyclopropylaminomethyl-piperidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one

[2029]

[2030] Yellow solid.

[2031] MS m/z 497.6 [M−1].

Example 414 4-(4-Chlorophenyl)-3-[1-[3-((S)-3-cyclopropylaminomethyl-piperidine-1carbonyl)-5-methyl-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[2032]

[2033] Yellow solid.

[2034] MS m/z 513.6 [M−1].

[2035]

Example 4152-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-methyl-amide

[2036]

[2037] Yellow solid.

[2038]¹H NMR (400 MHz, DMSO-d₆) δ 13.56 (s, 1H, NH), 11.01 (br s, 1H,NH), 7.46 (m, 1H), 7.24 (m, 1H), 7.17 (m, 3H), 6.91 (m, 1H), 6.85 (s,1H), 6.74 (d, 1H), 6.09 (s, 1H), 4.70 (m, 1H), 3.55 (m, 1H), 2.93 (m,1H), 2.83 (s, 3H, CH₃), 2.25 (m, 4H), 2.12 (m, 4H), 1.70 (m, 2H), 1.51(m, 3H).

[2039] MS m/z 503.4 [M⁺+1].

Example 4162-[4-(3-Fluoro-phenyl)-2-oxo1,2-dihydroindol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3-cyclopropylamino-2-hydroxy-propyl)-amide

[2040]

[2041] Yellow solid.

[2042]¹H NMR (400 MHz, DMSO-d6) o 13.85 (s, 1H, NH), 11.14 (s, 1H, NH),8.0 (s, 1H), 7.83 (t, 1H), 7.44 (m, 1H), 7.18 (m, 4H), 6.93 (dd, 1H),6.78 (dd, 1H), 6.42 (d, 1H), 3.61 (m, 1H), 3.14 (m, 2H), 3.02 (m, 2H),2.5-2.62 (m, 3H), 2.31 (s, 3H, CH₃), 2.13 (m, 2H).

[2043] MS m/z 475.2 [M⁺+1].

Example 4174-(3-Fluoro-phenyl)-3-[1-[4-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one

[2044]

[2045] 4-(2-Pyrrolidin- I -yl-ethyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (0.2 mmol) was condensed with4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (0.2 mmol) and piperidine (2drops) in ethanol at rt for overnight. The solvent was removed and theresidue was purified on a silica gel column to give 25 mg of the titledcompound as a yellow solid.

[2046]¹H NMR (400 MHz, CD₃0D) δ 7.52 (m, 1H), 7.14-7.24 (m, 4H), 6.94(d, 1H) , 6.8 (d, 1H), 6.74 (s, 1H), 6.07 (s, 1H), 3.22 (m, 4H), 3.12(m, 2H), 2.70 (m, 3H), 2.01 (m, 6H), 1.95 (m, 1H), 1.75 (m, 2H), 1.42(m, 1H).

[2047] MS m/z 456 [M⁺+1].

[2048]

[2049] Biological Evaluation

[2050] It will be appreciated that, in any given series of compounds, arange of biological activities will be observed. In its presentlypreferred aspects, this invention relates to novel 4-aryl substitutedindolinones capable of modulating, regulating and/or inhibiting proteinkinase activity. The following assays may be employed to select thosecompounds demonstrating the optimal degree of the desired activity.

[2051] I. Assay Procedures

[2052] The following in vitro assays may be used to determine the levelof activity and effect of the different compounds of the presentinvention on one or more of the PKs. Similar assays can be designedalong the same lines for any PK using techniques well known in the art.

[2053] Several of the assays described herein are performed in an ELISA(Enzyme-Linked Immunosorbent Sandwich Assay) format (Voller, et al.,1980, “Enzyme-Linked Immunosorbent Assay,” Manual of ClinicalImmunology, 2d ed., Rose and Friedman, Am. Soc. Of Microbiology,Washington, D.C., pp. 359-371). The general procedure is as follows: acompound is introduced to cells expressing the test kinase, eithernaturally or recombinantly, for a selected period of time after which,if the test kinase is a receptor, a ligand known to activate thereceptor is added. The cells are lysed and the lysate is transferred tothe wells of an ELISA plate previously coated with a specific antibodyrecognizing the substrate of the enzymatic phosphorylation reaction.Non-substrate components of the cell lysate are washed away and theamount of phosphorylation on the substrate is detected with an antibodyspecifically recognizing phosphotyrosine compared with control cellsthat were not contacted with a test compound.

[2054] The presently preferred protocols for conducting the ELISAexperiments for specific PKs is provided below. However, adaptation ofthese protocols for determining the activity of compounds against otherRTKs, as well as for CTKs and STKs, is well within the scope ofknowledge of those skilled in the art. Other assays described hereinmeasure the amount of DNA made in response to activation of a testkinase, which is a general measure of a proliferative response. Thegeneral procedure for this assay is as follows: a compound is introducedto cells expressing the test kinase, either naturally or recombinantly,for a selected period of time after which, if the test kinase is areceptor, a ligand known to activate the receptor is added. Afterincubation at least overnight, a DNA labeling reagent such as5-bromodeoxyuridine (BrdU) or H³-thymidine is added. The amount oflabeled DNA is detected with either an anti-BrdU antibody or bymeasuring radioactivity and is compared to control cells not contactedwith a test compound.

[2055] GST-FLK-1 BIOASSAY

[2056] This assay analyzes the tyrosine kinase activity of GST-Flk1 onpoly(glu-tyr) peptides.

[2057] Materials and Reagents:

[2058] 1. Corning 96-well ELISA plates (Corning Catalog No. 25805-96).

[2059] 2. poly(glu-tyr) 4:1, lyophilizate (Sigma Catalog No. P0275), 1mg/ml in sterile PBS.

[2060] 3. PBS Buffer: for 1 L, mix 0.2 g KH₂PO₄, 1.15 g Na₂HPO₄, 0.2 gKCl and 8 g NaCl in approx. 900ml dH₂O. When all reagents havedissolved, adjust the pH to 7.2 with HCl. Bring total volume to 1 L withdH₂O.

[2061] 4. PBST Buffer: to 1 L of PBS Buffer, add 1.0 ml Tween-20.

[2062] 5. TBB—Blocking Buffer: for 1 L, mix 1.21 g TRIS, 8.77 g NaCl, 1ml TWEEN-20 in approximately 900 ml dH₂O. Adjust pH to 7.2 with HCl. Add10 g BSA, stir to dissolve. Bring total volume to 1 L with dH₂O. Filterto remove particulate matter.

[2063] 6. 1% BSA in PBS: add 10 g BSA to approx. 990 ml PBS buffer, stirto dissolve. Adjust total volume to 1 L with PBS buffer, filter toremove particulate matter.

[2064] 7. 50 mM Hepes pH 7.5.

[2065] 8. GST-Flk1ed purified from sf9 recombinant baculovirustransformation (SUGEN, Inc.).

[2066] 9. 4% DMSO in dH₂O.

[2067] 10. 10 mM ATP in dH₂O.

[2068] 11. 40 mM MnCl₂

[2069] 12. Kinase Dilution Buffer (KDB): mix 10 ml Hepes (pH 7.5), 1 ml5 M NaCl, 40 μL 100 mM sodium orthovanadate and 0.4 ml of 5% BSA in dH₂Owith 88.56 ml dH₂O.

[2070] 13. NUNC 96-well V bottom polypropylene plates, AppliedScientific Catalog # AS-72092

[2071] 14. EDTA: mix 14.12 g ethylenediaminetetraacetic acid (EDTA) withapprox. 70 ml dH₂O. Add 10 N NaOH until EDTA dissolves. Adjust pH to8.0. Adjust total volume to 100 ml with dH₂O.

[2072] 15. 1⁰ and 2⁰ Antibody Dilution Buffer: mix 10 ml of5% BSA in PBSbuffer with 89.5 ml TBST.

[2073] 16. Anti-phosphotyrosine rabbit polyclonal antisera (SUGEN, Inc.)

[2074] 17. Goat anti-rabbit HRP conjugate.

[2075] 18. ABST solution: To approx. 900 ml dH₂O add 19.21 g citric acidand 35.49 g Na₂HPO₄. Adjust pH to 4.0 with phosphoric acid. Add2,2°-Azinobis(3-ethyl- benzthiazoline-6-sulfonic acid (ABTS, Sigma, Cat.No. A-1888, hold for approx. ½ hour, filter.

[2076] 19. 30% Hydrogen Peroxide.

[2077] 20. ABST/H₂O₂: add 3 μl of H₂O₂ to 15 ml of ABST solution.

[2078] 21. 0.2 M HCl.

[2079] Procedure:

[2080] 1. Coat Coming 96-well ELISA plates with 2 μg of polyEY in 100 μlPBS/well, hold at room temperature for 2 hours or at 4° C. overnight.Cover plates to prevent evaporation.

[2081] 2. Remove unbound liquid from wells by inverting plate. Wash oncewith TBST. Pat the plate on a paper towel to remove excess liquid.

[2082]3. Add 100 μl of 1% BSA in PBS to each well. Incubate, withshaking, for 1 hr. at room temperature.

[2083] 4. Repeat step 2.

[2084] 5. Soak wells with 50 mM HEPES (pH 7.5, 150 μl/well).

[2085] 6. Dilute test compound with dH₂O/4% DMSO to 4 times the desiredfinal assay concentration in 96-well polypropylene plates.

[2086] 7. Add 25 ill diluted test compound to each well of ELISA plate.In control wells, place 25 μl of dH₂O/4% DMSO.

[2087] 8. Dilute GST-Flk1 0.005 μg (5 ng)/well in KDB.

[2088] 9. Add 50 μl of diluted enzyme to each well.

[2089] 10. Add 25 μl 0.5 M EDTA to negative control wells.

[2090] 11. Add 25 μl of 40 mM MnCl₂ with 4× ATP (2 μM) to all wells (100μl final volume, 0.5 μM ATP final concentration in each well).

[2091] 12. Incubate, with shaking, for 15 minutes at room temperature.

[2092] 13. Stop reaction by adding 25 μl of 500 mM EDTA to each well.

[2093] 14. Wash 3× with TBST and pat plate on paper towel to removeexcess liquid.

[2094] 15. Add 100 μl per well anti-phosphotyrosine antisera, 1:10,000dilution in antibody dilution buffer. Incubate, with shaking, for 90min. at room temperature.

[2095] 16. Wash as in step 14.

[2096]17. Add 100 μl/well of goat anti-rabbit HRP conjugate (1:6,000 inantibody dilution buffer). Incubate, with shaking, for 90 minutes areroom temperature.

[2097] 18. Wash as in Step 14.

[2098] 19. Add 100 μl room temperature ABST/H₂O₂ solution to each well.

[2099] 20. Incubate, with shaking for 15 to 30 minutes at roomtemperature.

[2100] 21. If necessary, stop reaction by adding 100 μl of 0.2 M HCl toeach well.

[2101] 22. Read results on Dynatech MR7000 ELISA reader with test filterat 410 nM and reference filter at 630 nM.

[2102] PYK2 BIOASSAY

[2103] This assay is used to measure the in vitro kinase activity of HAepitope-tagged full length pyk2 (FL.pyk2-HA) in an ELISA assay.

[2104] Materials and Reagents:

[2105] 1. Coming 96-well ELISA plates.

[2106] 2. 12CA5 monoclonal anti-HA antibody (SUGEN, Inc.)

[2107] 3. PBS (Dulbecco's Phosphate-Buffered Saline (Gibco Catalog #450- 1300EB)

[2108] 4. TBST Buffer: for 1 L, mix 8.766 g NaCl, 6.057 g TRIS and 1 mlof 0.1% Triton X-100 in approx. 900 ml dH₂O. Adjust pH to 7.2, bringvolume to 1 L.

[2109] 5. Blocking Buffer: for 1 L, mix 100 g 10% BSA, 12.1 g 100 mMTRIS, 58.44 g 1 M NaCl and 10 mL of 1% TWEEN-20.

[2110] 6. FL.pyk2-HA from sf9 cell lysates (SUGEN, Inc.).

[2111] 7. 4% DMSO in MilliQue H₂O.

[2112] 8. 10 mM ATP in dH₂O.

[2113] 9. 1 M MnCl₂.

[2114] 10. 1 M MgCl₂.

[2115] 11. 1 M Dithiothreitol (DTT).

[2116] 12. 10× Kinase buffer phosphorylation: mix 5.0 ml 1 M Hepes (pH7.5), 0.2 ml 1 M MnCl₂, 1.0 ml 1 M MgCl₂, 1.0 ml 10% Triton X-100 in 2.8ml dH₂O. Just prior to use, add 0.1 ml 1 M DTT.

[2117] 13. NUNC 96-well V bottom polypropylene plates.

[2118] 14. 500 mM EDTA in dH₂O.

[2119] 15. Antibody dilution buffer: for 100 mL, 1 mL 5% BSA/PBS and 1mL 10% Tween-20 in 88 mL TBS.

[2120] 16. HRP-conjugated anti-Ptyr (PY99, Santa Cruz Biotech Cat. No.SC-7020).

[2121] 17. ABTS, Moss, Cat. No. ABST-2000.

[2122] 18. 10% SDS.

[2123] Procedure:

[2124] 1. Coat Corning 96 well ELISA plates with 0.5 μg per well 12CA5anti-HA antibody in 100 μl PBS. Store overnight at 4° C.

[2125] 2. Remove unbound HA antibody from wells by inverting plate. Washplate with dH₂O. Pat the plate on a paper towel to remove excess liquid.

[2126] 3. Add 150 μl Blocking Buffer to each well. Incubate, withshaking, for 30 min at room temperature.

[2127] 4. Wash plate 4× with TBS-T.

[2128] 5. Dilute lysate in PBS (1.5 pg lysate/100 μl PBS).

[2129] 6. Add 100 μl of diluted lysate to each well. Shake at roomtemperature for 1 hr.

[2130] 7. Wash as in step 4.

[2131] 8. Add 50 μl of 2× kinase Buffer to ELISA plate containingcaptured pyk2-HA.

[2132] 9. Add 25 μL of 400 μM test compound in 4% DMSO to each well. Forcontrol wells use 4% DMSO alone.

[2133] 10. Add 25 μL of 0.5 M EDTA to negative control wells.

[2134] 11. Add 25 μl of 20 μM ATP to all wells. Incubate, with shaking,for 10 minutes.

[2135] 12. Stop reaction by adding 25 μl 500 mM EDTA (pH 8.0) to allwells.

[2136] 13. Wash as in step 4.

[2137] 14. Add 100 μL HRP conjugated anti-Ptyr diluted 1:6000 inAntibody Dilution Buffer to each well. Incubate, with shaking, for 1 hr.at room temperature.

[2138] 15. Wash plate 3× with TBST and 1× with PBS.

[2139] 16. Add 100 μL of ABST solution to each well.

[2140] 17. If necessary, stop the development reaction by adding 20 μL10% SDS to each well.

[2141] 18. Read plate on ELISA reader with test filter at 410 nM andreference filter at 630 nM.

[2142] FGFR1 BIOASSAY

[2143] This assay is used to measure the in vitro kinase activity ofFGF1-R in an ELISA assay.

[2144] Materials and Reagents:

[2145] 1. Costar 96-well ELISA plates (Coming Catalog # 3369).

[2146] 2. Poly(Glu-Tyr) (Sigma Catalog # P0275).

[2147] 3. PBS (Gibco Catalog # 450-1300EB)

[2148] 4. 50 mM Hepes Buffer Solution.

[2149] 5. Blocking Buffer (5% BSA/PBS).

[2150] 6. Purified GST-FGFR1 (SUGEN, Inc.)

[2151] 7. Kinase Dilution Buffer. Mix 500 μl M Hepes (GIBCO), 20 μl 5%BSA/PBS, 10 μl 100 mM sodium orthovanadate and 50 μl 5M NaCl.

[2152] 8. 10 mM ATP

[2153] 9. ATP/MnCl₂ phosphorylation mix: mix 20 μL ATP, 400 μL 1 M MnCl₂and 9.56 ml dH₂O.

[2154] 10. NUNC 96-well V bottom polypropylene plates (AppliedScientific Catalog # AS-72092).

[2155] 11. 0.5M EDTA.

[2156] 12. 0.05% TBST Add 500 μL TWEEN to 1 liter TBS.

[2157] 13. Rabbit polyclonal anti-phosphotyrosine serum (SUGEN, Inc.).

[2158] 14. Goat anti-rabbit IgG peroxidase conjugate (Biosource, Catalog# AL10404).

[2159] 15. ABTS Solution.

[2160] 16. ABTS/H₂O₂ solution.

[2161] Procedure:

[2162] 1. Coat Costar 96 well ELISA plates with 1 μg per wellPoly(Glu-Tyr) in 100 μl PBS. Store overnight at 4° C.

[2163] 2. Wash coated plates once with PBS.

[2164] 3. Add 150 μL of 5%BSA/PBS Blocking Buffer to each well.Incubate, with shaking, for 1 hr at room temperature.

[2165] 4. Wash plate 2× with PBS, then once with 50mM Hepes. Pat plateson a paper towel to remove excess liquid and bubbles.

[2166] 5. Add 25μL of 0.4 mM test compound in 4% DMSO or 4% DMSO alone(controls) to plate.

[2167] 6. Dilute purified GST-FGFR1 in Kinase Dilution Buffer (5 ngkinase/50μl KDB/well).

[2168] 7. Add 50μL of diluted kinase to each well.

[2169] 8. Start kinase reaction by adding 25 μl/well of freshly preparedATP/Mn ++(0.4 ml 1 M MnCl₂, 40 μL 10 mM ATP, 9.56 ml dH₂O), freshlyprepared).

[2170] 9. Stop reaction with 25 μL of 0.5M EDTA.

[2171] 10. Wash plate 4× with fresh TBST.

[2172] 11. Make up Antibody Dilution Buffer: For 50 ml, mix 5 ml of 5%BSA, 250 μl of 5% milk and 50 μl of 100 mM sodium vanadate, bring tofinal volume with 0.05% TBST.

[2173] 12. Add 100 μl per well of anti-phosphotyrosine (1:10000 dilutionin ADB). Incubate, with shaking for 1 hr. at room temperature.

[2174] 13. Wash as in step 10.

[2175] 14. Add 100 μl per well of Biosource Goat anti-rabbit IgGperoxidase conjugate (1:6000 dilution in ADB). Incubate, with shakingfor 1 hr. at room temperature.

[2176] 15. Wash as in step 10 and then with PBS to remove bubbles andexcess TWEEN.

[2177] 16. Add 100 μl of ABTS/H₂O₂ solution to each well.

[2178] 17. Incubate, with shaking, for 10 to 20 minutes. Remove anybubbles.

[2179] 18. Read assay on Dynatech MR7000 ELISA reader: test filter at410 nM, reference filter at 630 nM.

[2180] PDGFR BIOASSAY

[2181] This assay is used to the in vitro kinase activity of PDGFR in anELISA assay.

[2182] Materials and Reagents:

[2183] 1. Corning 96-well ELISA plates

[2184] 2. 28D4C10 monoclonal anti-PDGFR antibody (SUGEN, Inc.).

[2185] 3. PBS.

[2186] 4. TBST Buffer.

[2187] 5. Blocking Buffer (same as for EGFR bioassay).

[2188] 6. PDGFR-β expressing NIH 3T3 cell lysate (SUGEN, Inc.).

[2189] 7. TBS Buffer.

[2190] 8. TBS+10% DMSO.

[2191] 9. ATP.

[2192] 10. MnCl₂.

[2193] 11. Kinase buffer phosphorylation mix: for 10 ml, mix 250 μl 1 MTRIS, 200 μl 5M NaCl, 100 μl 1 M MnCl₂ and 50 μl 100 mM Triton X-100 inenough dH₂O to make 10 ml.

[2194] 12. NUJNC 96-well V bottom polypropylene plates.

[2195] 13. EDTA.

[2196] 14. Rabbit polyclonal anti-phosphotyrosine serum (SUGEN, Inc.).

[2197] 15. Goat anti-rabbit IgG peroxidase conjugate (Biosource Cat. No.AL10404).

[2198] 16. ABTS.

[2199] 17. Hydrogen peroxide, 30% solution.

[2200] 18. ABTS/H₂O₂.

[2201] 19. 0.2 M HCl.

[2202] Procedure:

[2203] 1. Coat Coming 96 well ELISA plates with 0.5 μg 28D4C10 in 100 μlPBS per well, hold overnight at 4° C.

[2204] 2. Remove unbound 28D4C10 from wells by inverting plate to removeliquid. Wash 1× with dH₂O. Pat the plate on a paper towel to removeexcess liquid.

[2205] 3. Add 150 μl of Blocking Buffer to each well. Incubate for 30min. at room temperature with shaking.

[2206] 4. Wash plate 3× with deionized water, then once with TBST. Patplate on a paper towel to remove excess liquid and bubbles.

[2207] 5. Dilute lysate in HNTG (10 μg lysate/100 μl HNTG).

[2208] 6. Add 100 μl of diluted lysate to each well. Shake at roomtemperature for 60 min.

[2209] 7. Wash plates as described in Step 4.

[2210] 8. Add 80 μl working kinase buffer mix to ELISA plate containingcaptured PDGFR.

[2211] 9. Dilute test compound 1:10 in TBS in 96-well polypropyleneplates.

[2212] 10. Add 10 μl diluted test compound to ELISA plate. To controlwells, add 10 μl TBS+10% DMSO. Incubate with shaking for 30 minutes atroom temperature.

[2213] 11. Add 10 μl ATP directly to all wells except negative controlwell (final well volume should be approximately 100 μl with 20 μM ATP ineach well.) Incubate 30 minutes with shaking.

[2214] 12. Stop reaction by adding 10 μl of EDTA solution to each well.

[2215] 13. Wash 4× with deionized water, twice with TBST.

[2216] 14. Add 100 μl anti-phosphotyrosine (1:3000 dilution in TBST) perwell. Incubate with shaking for 30-45 min. at room temperature.

[2217] 15. Wash as in Step 4.

[2218] 16. Add 100 μl Biosource Goat anti-rabbit IgG peroxidaseconjugate (1:2000 dilution in TBST) to each well. Incubate with shakingfor 30 min. at room temperature.

[2219] 17. Wash as in Step 4.

[2220] 18. Add 100 μl of ABTS/H₂O₂ solution to each well.

[2221] 19. Incubate 10 to 30 minutes with shaking. Remove any bubbles.

[2222] 20. If necessary stop reaction with the addition of 100 μl 0.2 MHCl per well.

[2223] 21. Read assay on Dynatech MR7000 ELISA reader with test filterat 410 nM and reference filter at 630 nM.

[2224] CELLULAR HER-2 KINASE ASSAY

[2225] This assay is used to measure HER-2 kinase activity in wholecells in an ELISA format.

[2226] Materials and Reagents:

[2227] 1. DMEM (GIBCO Catalog #11965-092).

[2228] 2. Fetal Bovine Serum (FBS, GIBCO Catalog #16000-044), heatinactivated in a water bath for 30 min. at 56° C.

[2229] 3. Trypsin (GIBCO Catalog #25200-056).

[2230] 4. L-Glutamine (GIBCO Catalog #25030-081).

[2231] 5. HEPES (GIBCO Catalog #15630-080).

[2232] 6. Growth Media: Mix 500 ml DMEM, 55 ml heat inactivated FBS, 10ml HEPES and 5.5 ml L-Glutamine.

[2233] 7. Starve Media: Mix 500 ml DMEM, 2.5 ml heat inactivated FBS, 10ml HEPES and 5.5 ml L-Glutamine.

[2234] 8. PBS.

[2235] 9. Flat Bottom 96-well Tissue Culture Micro Titer Plates (ComingCatalog # 25860).

[2236] 10. 15 cm Tissue Culture Dishes (Coming Catalog #08757148).

[2237] 11. Coming 96-well ELISA Plates.

[2238] 12. NUNC 96-well V bottom polypropylene plates.

[2239] 13. Costar Transfer Cartridges for the Transtar 96 (CostarCatalog #7610).

[2240] 14. SUMO 1: monoclonal anti-EGFR antibody (SUGEN, Inc.).

[2241] 15. TBST Buffer.

[2242] 16. Blocking Buffer: 5% Carnation Instant Milk® in PBS.

[2243] 17. EGF Ligand: EGF-201, Shinko American, Japan. Suspend powderin 100 μL of 10 mM HCl. Add 100 μL 10 mM NaOH. Add 800 μL PBS andtransfer to an Eppendorf tube, store at −20° C. until ready to use.

[2244] 18. HNTG Lysis Buffer: For Stock 5× HNTG, mix 23.83 g Hepes,43.83 g NaCl, 500 ml glycerol and 100 ml Triton X-100 and enough dH₂O tomake 1 L of total solution. For 1× HNTG*, mix 2 ml 5× HNTG, 100 μL 0.1 MNa₃VO₄, 250 μL 0.2M Na₄P₂O₇ and 100 μL EDTA.

[2245] 19. EDTA.

[2246] 20. Na₃VO₄: To make stock solution, mix 1.84 g Na₃VO₄ with 90 mldH₂O. Adjust pH to 10. Boil in microwave for one minute (solutionbecomes clear). Cool to room temperature. Adjust pH to 10. Repeatheating/cooling cycle until pH remains at 10.

[2247] 21. 200 mM Na₄P₂O₇.

[2248] 22. Rabbit polyclonal antiserum specific for phosphotyrosine(anti-Ptyr antibody, SUGEN, Inc.).

[2249] 23. Affinity purified antiserum, goat anti-rabbit IgG antibody,peroxidase conjugate (Biosource Cat # AL10404).

[2250] 24. ABTS Solution.

[2251] 25. 30 % Hydrogen peroxide solution.

[2252] 26. ABTS/H₂O₂.

[2253] 27. 0.2 M HCl.

[2254] Procedure:

[2255] 1. Coat Corning 96 well ELISA plates with SUM01 at 1.0 μg perwell in PBS, 100 μl final volume/well. Store overnight at 4° C.

[2256] 2. On day of use, remove coating buffer and wash plate 3 timeswith dH₂O and once with TBST buffer. All washes in this assay should bedone in this manner, unless otherwise specified.

[2257] 3. Add 100 μL of Blocking Buffer to each well. Incubate plate,with shaking, for 30 min. at room temperature. Just prior to use, washplate.

[2258] 4. Use EGFr/HER-2 chimera/3T3-C7 cell line for this assay.

[2259] 5. Choose dishes having 80-90 % confluence. Collect cells bytrypsinization and centrifuge at 1000 rpm at room, temperature for 5min.

[2260] 6. Resuspend cells in starve medium and count with trypan blue.Viability above 90% is required. Seed cells in starve medium at adensity of 2,500 cells per well, 90 μL per well, in a 96 well microtiterplate. Incubate seeded cells overnight at 37° under 5% CO₂.

[2261] 7. Start the assay two days after seeding.

[2262] 8. Test compounds are dissolved in 4% DMSO. Samples are thenfurther diluted directly on plates with starve-DMEM. Typically, thisdilution will be 1:10 or greater. All wells are then transferred to thecell plate at a further 1:10 dilution (10 μl sample and media into 90 μlof starve media). The final DMSO concentration should be 1% or lower. Astandard serial dilution may also be used.

[2263] 9. Incubate under 5% CO₂ at 37° C. for 2 hours.

[2264] 10. Prepare EGF ligand by diluting stock EGF (16.5 μM) in warmDMEM to 150 nM.

[2265] 11. Prepare fresh HNTG* sufficient for 100 μL per well; place onice.

[2266] 12. After 2 hour incubation with test compound, add prepared EGFligand to cells, 50 μL per well, for a final concentration of 50 nM.Positive control wells receive the same amount of EGF. Negative controlsdo not receive EGF. Incubate at 37° C. for 10 min.

[2267] 13. Remove test compound, EGF, and DMEM. Wash cells once withPBS.

[2268] 14. Transfer HNTG* to cells, 100 μL per well. Place on ice for 5minutes. Meanwhile, remove blocking buffer from ELISA plate and wash.

[2269] 15. Scrape cells from plate with a micropipettor and homogenizecell material by repeatedly aspirating and dispensing the HNTG* lysisbuffer. Transfer lysate to a coated, blocked, washed ELISA plate.

[2270] 16. Incubate, with shaking, at room temperature for 1 hr.

[2271] 17. Remove lysate, wash. Transfer freshly diluted anti-Ptyrantibody (1:3000 in TBST) to ELISA plate, 100 μL per well.

[2272] 18. Incubate, with shaking, at room temperature, for 30 min.

[2273] 19. Remove anti-Ptyr antibody, wash. Transfer freshly dilutedBIOSOURCE antibody to ELISA plate(1:8000 in TBST, 100 μL per well).

[2274] 20. Incubate, with shaking, at room temperature for 30 min.

[2275] 21. Remove BIOSOURCE antibody, wash. Transfer freshly preparedABTS/H₂O₂ solution to ELISA plate, 100 μL per well.

[2276] 22. Incubate, with shaking, for 5-10 minutes. Remove any bubbles.

[2277] 23. Stop reaction by adding 100 μL of 0.2M HCl per well.

[2278] 24. Read assay on Dynatech MR7000 ELISA reader with test filterset at 410 nM and reference filter at 630 nM.

[2279] CDK2/CYCLIN A ASSAY

[2280] This assay is used to measure the in vitro serine/threoninekinase activity of human cdk2/cyclin A in a Scintillation ProximityAssay (SPA).

[2281] Materials and Reagents.

[2282] 1. Wallac 96-well polyethylene terephthalate (flexi) plates(Wallac Catalog # 1450-401).

[2283] 2. Amersham Redivue [λ³³P]ATP (Amersham catalog #AH 9968).

[2284] 3. Amersham streptavidin coated polyvinyltoluene SPA beads(Amersham catalog #RPNQ0007). The beads should be reconstituted in PBSwithout magnesium or calcium, at 20 mg/ml.

[2285] 4. Activated cdk2/cyclin A enzyme complex purified from Sf9 cells(SUGEN, Inc.).

[2286] 5. Biotinylated peptide substrate (Debtide). Peptidebiotin-X-PKTPKKAKKL is dissolved in dH₂O at a concentration of 5 mg/ml.

[2287] 6. 20% DMSO in dH₂O.

[2288] 7. Kinase buffer: for 10 ml, mix 9.1 ml dH₂O, 0.5 ml TRIS(pH7.4), 0.2 ml 1 M MgCl_(2+B, 0.2) ml 10% NP40 and 0.02 ml 1 M DTT, addedfresh just prior to use.

[2289] 8. 10 mM ATP in dH₂O.

[2290] 9. 1 M Tris, pH adjusted to 7.4 with HCl.

[2291] 10. 1 M MgCl₂.

[2292] 11. 1 M DTT.

[2293] 12. PBS (Gibco Catalog # 14190-144).

[2294] 13. 0.5 M EDTA.

[2295] 14. Stop solution: For 10 ml, mix 9.25 ml PBS, 0.05 ml 10 mM ATP,0.1 ml 0.5 M EDTA, 0.1 ml 10% Triton X-100 and 1.5 ml of 50 mg/ml SPAbeads.

[2296] Procedure:

[2297] 1. Prepare solutions of test compounds at 4× the desired finalconcentration in 5% DMSO. Add 10 μL to each well. For positive andnegative controls, use 10 μL 20% DMSO alone in wells.

[2298] 2. Dilute the peptide substrate (deb-tide) 1:250 with dH₂O togive a final concentration of 0.02 mg/ml.

[2299] 3. Mix 24 μL 0.1 mM ATP with 24 μCi λ³³P ATP and enough dH₂O tomake 600 μL.

[2300] 4. Mix diluted peptide and ATP solutions 1:1 (600 μL+600 μL perplate). Add 10 μL of this solution to each well.

[2301] 5. Dilute 5 μL of cdk2/cyclin A solution into 2.1 ml 2× kinasebuffer (per plate). Add 20 μL enzyme per well. For negative controls,add 20 μL 2× kinase buffer without enzyme.

[2302] 6. Mix briefly on a plate shaker; incubate for 60 minutes.

[2303] 7. Add 200 μL stop solution per well.

[2304] 8. Let stand at least 10 min.

[2305] 9. Spin plate at approx. 2300 rpm for 10-15 min.

[2306] 10. Count plate on Trilux reader.

[2307] MET TRANSPHOSPHORYLATION ASSAY

[2308] This assay is used to measure phosphotyrosine levels on apoly(glutamic acid:tyrosine, 4:1) substrate as a means for identifyingagonists/antagonists of met transphosphorylation of the substrate.

[2309] Materials and Reagents:

[2310] 1. Coming 96-well ELISA plates, Coming Catalog # 25805-96.

[2311] 2. Poly(glu-tyr), 4:1, Sigma, Cat. No; P 0275.

[2312] 3. PBS, Gibco Catalog # 450-1300EB

[2313] 4. 50 mM HEPES

[2314] 5. Blocking Buffer: Dissolve 25 g Bovine Serum Albumin, SigmaCat. No A-7888, in 500 ml PBS, filter through a 4 μm filter.

[2315] 6. Purified GST fusion protein containing the Met kinase domain,SUGEN, Inc.

[2316] 7. TBST Buffer.

[2317] 8. 10% aqueous (MilliQue H₂O) DMSO.

[2318] 9. 10 mM aqueous (dH₂O) Adenosine-5°-triphosphate, Sigma Cat. No.A-5394.

[2319] 10. 2× Kinase Dilution Buffer: for 100 ml, mix 10 mL 1 M HEPES atpH 7.5 with 0.4 mL 5% BSAIPBS, 0.2 mL 0.1 M sodium orthovanadate and 1mL SM sodium chloride in 88.4 mL dH₂O.

[2320] 11. 4× ATP Reaction Mixture: for 10 mL, mix 0.4 mL 1 M manganesechloride and 0.02 mL 0.1 M ATP in 9.56 mL dH₂O.

[2321] 12. 4× Negative Controls Mixture: for 10 mL, mix 0.4 mL 1 Mmanganese chloride in 9.6 mL dH₂O.

[2322] 13. NUNC 96-well V bottom polypropylene plates, AppliedScientific Catalog # S-72092

[2323] 14. 500 mM EDTA.

[2324] 15. Antibody Dilution Buffer: for 100 mL, mix 10 mL 5% BSA/PBS,0.5 mL 5% Carnatione Instant Milk in PBS and 0.1 mL 0.1 M sodiumorthovanadate in 88.4 mL TBST.

[2325] 16. Rabbit polyclonal antophosphotyrosine antibody, SUGEN, Inc.

[2326] 17. Goat anti-rabbit horseradish peroxidase conjugated antibody,Biosource, Inc.

[2327] 18. ABTS Solution: for 1 L, mix 19.21 g citric acid, 35.49 gNa₂HPO₄ and 500 mg ABTS with sufficient dH₂O to make 1 L.

[2328] 19. ABTS/H₂O₂: mix 15 mL ABST solution with 2 μL H₂O₂ fiveminutes before use.

[2329] 20. 0.2 M HCl

[2330] Procedure:

[2331] 1. Coat ELISA plates with 2 μg Poly(Glu-Tyr) in 100 μL PBS, holdovernight at 4 ° C.

[2332] 2. Block plate with 150 μL of 5% BSA/PBS for 60 min.

[2333] 3. Wash plate twice with PBS then once with 50 mM Hepes buffer pH7.4.

[2334] 4. Add 50 μl of the diluted kinase to all wells. (Purified kinaseis diluted with Kinase Dilution Buffer. Final concentration should be 10ng/well.)

[2335] 5. Add 25 μL of the test compound (in 4% DMSO) or DMSO alone (4%in dH₂O) for controls to plate.

[2336] 6. Incubate the kinase/compound mixture for 15 minutes.

[2337] 7. Add 25 μL of 40 mM MnCl₂ to the negative control wells.

[2338] 8. Add 25 μL ATP/MnCl₂ mixture to the all other wells (except thenegative controls). Incubate for 5 min.

[2339] 9. Add 25 μL 500 mM EDTA to stop reaction.

[2340] 10. Wash plate 3× with TBST.

[2341] 11. Add 100 μL rabbit polyclonal anti-Ptyr diluted 1:10,000 inAntibody Dilution Buffer to each well. Incubate, with shaking, at roomtemperature for one hour.

[2342] 12. Wash plate 3× with TBST.

[2343] 13. Dilute Biosource HRP conjugated anti-rabbit antibody 1:6,000in Antibody Dilution buffer. Add 100 μL per well and incubate at roomtemperature, with shaking, for one hour.

[2344] 14. Wash plate IX with PBS.

[2345] 15. Add 100 μl of ABTS/H₂O₂ solution to each well.

[2346] 16. If necessary, stop the development reaction with the additionof 100 μl of 0.2M HCl per well.

[2347] 17. Read plate on Dynatech MR7000 ELISA reader with the testfilter at 410 nM and the reference filter at 630 nM.

[2348] IGF-1 Transphosphorylation Assay

[2349] This assay is used to measure the phosphotyrosine level inpoly(glutamic acid:tyrosine, 4:1) for the identification ofagonists/antagonists of gst-IGF-1 transphosphorylation of a substrate.

[2350] Materials and Reagents:

[2351] 1. Coming 96-well ELISA plates.

[2352] 2. Poly(Glu-Tyr),4:1, Sigma Cat. No. P 0275.

[2353] 3. PBS, Gibco Catalog #450-1300EB.

[2354] 4. 50 mM HEPES

[2355] 5. TBB Blocking Buffer: for 1 L, mix 100 g BSA, 12.1 gTRIS (pH7.5), 58.44 g sodium chloride and 10 mL 1%TWEEN-20.

[2356] 6. Purified GST fusion protein containing the IGF-1 kinase domain(SUGEN, Inc.)

[2357] 7. TBST Buffer: for 1 L, mix 6.057 g Tris, 8.766 g sodiumchloride and 0.5 ml TWEEN-20 with enough dH₂O to make 1 liter.

[2358] 8. 4% DMSO in Milli-Q H₂O.

[2359] 9. 10 mM ATP in dH₂O.

[2360] 10. 2× Kinase Dilution Buffer: for 100 mL, mix 10 mL 1 M HEPES(pH 7.5), 0.4 mL 5% BSA in dH₂O, 0.2 mL 0.1 M sodium orthovanadate and 1mL 5 M sodium chloride with enough dH₂O to make 100 mL.

[2361] 11. 4× ATP Reaction Mixture: for 10 mL, mix 0.4 mL 1 M MnCl₂ and0.008 mL 0.01 M ATP and 9.56 mL dH₂O.

[2362] 12. 4× Negative Controls Mixture: mix 0.4 mL 1 M MnCl₂ in 9.60 mLdH₂O.

[2363] 13. NUNC 96-well V bottom polypropylene plates.

[2364] 14. 500 mM EDTA in dH₂O.

[2365] 15. Antibody Dilution Buffer: for 100 mL, mix 10 mL 5% BSA inPBS, 0.5 mL 5% Carnation Instant Non-fat Milk in PBS and 0.1 mL 0.1 Msodium orthovanadate in 88.4 mL TBST.

[2366] 16. Rabbit Polyclonal antiphosphotyrosine antibody, SUGEN, Inc.

[2367] 17. Goat anti-rabbit HRP conjugated antibody, Biosource.

[2368] 18. ABTS Solution.

[2369] 20. ABTS/H₂O₂: mix 15 mL ABTS with 2 μL H₂O₂ 5 minutes beforeusing.

[2370] 21. 0.2 M HCl in dH₂O.

[2371] Procedure:

[2372] 1. Coat ELISA plate with 2.0 μg/well Poly(Glu, Tyr), 4:1 (SigmaP0275) in 100 μl PBS. Store plate overnight at 4° C.

[2373] 2. Wash plate once with PBS.

[2374] 3. Add 100 μl of TBB Blocking Buffer to each well. Incubate platefor 1 hour with shaking at room temperature.

[2375] 4. Wash plate once with PBS, then twice with 50 mM Hepes bufferpH 7.5.

[2376] 5. Add 25 μL of test compound in 4% DMSO (obtained by diluting astock solution of 10 mM test compound in 100% DMSO with dH20) to plate.

[2377] 6. Add 10.0 ng of gst-IGF-1 kinase in 50 μl Kinase DilutionBuffer to all wells.

[2378] 7. Start kinase reaction by adding 25 μl 4× ATP Reaction Mixtureto all test wells and positive control wells. Add 25 μl 4× NegativeControls Mixture to all negative control wells. Incubates for 10minutes, with shaking, at room temperature.

[2379] 8. Add 25 μl 0.5M EDTA (pH 8.0) to all wells.

[2380] 9. Wash plate 4× with TBST Buffer.

[2381] 10. Add rabbit polyclonal anti-phosphotyrosine antisera at adilution of 1:10,000 in 100 μl Antibody Dilution Buffer to all wells.Incubate, with shaking, at room temperature for 1 hour.

[2382] 11. Wash plate as in step 9.

[2383] 12. Add 100 μL Biosource anti-rabbit HRP at a dilution of1:10,000 in Antibody dilution buffer to all wells. Incubate, withshaking, at room temperature for 1 hour.

[2384] 13. Wash plate as in step 9, follow with one wash with PBS toremove bubbles and excess Tween-20.

[2385] 14. Develop by adding 100 μl/well ABTS/H₂O₂ to each well

[2386] 15. After about 5 minutes, read on ELISA reader with test filterat 410 nm and referenced filter at 630 nm.

[2387] BrdU INCORPORATION ASSAYS

[2388] The following assays use cells engineered to express a selectedreceptor and then evaluate the effect of a compound of interest on theactivity of ligand-induced DNA synthesis by determining BrdUincorporation into the DNA.

[2389] The following materials, reagents and procedure are general toeach of the following BrdU incorporation assays. Variances in specificassays are noted.

[2390] General Materials and Reagents:

[2391] 1. The appropriate ligand.

[2392] 2. The appropriate engineered cells.

[2393] 3. BrdU Labeling Reagent: 10 mM, in PBS, pH 7.4(Roche MolecularBiochemicals, Indianapolis, Ind.).

[2394] 4. FixDenat: fixation solution (Roche Molecular Biochemicals,Indianapolis, Ind.).

[2395] 5. Anti-BrdU-POD: mouse monoclonal antibody conjugated withperoxidase (Chemicon, Temecula, Calif.).

[2396] 6. TMB Substrate Solution: tetramethylbenzidine (TMB, ready touse, Roche Molecular Biochemicals, Indianapolis, Ind.).

[2397]7. PBS Washing Solution: 1× PBS, pH 7.4.

[2398]8. Albumin, Bovine (BSA), fraction V powder (Sigma Chemical Co.,USA).

[2399] General Procedure:

[2400] 1. Cells are seeded at 8000 cells/well in 10% CS, 2 mM Gln inDMEM, in a 96 well plate. Cells are incubated overnight at 37° C. in 5%CO₂.

[2401] 2. After 24 hours, the cells are washed with PBS, and then areserum-starved in serum free medium (0%CS DMEM with 0.1% BSA) for 24hours.

[2402] 3. On day 3, the appropriate ligand and the test compound areadded to the cells simultaneously. The negative control wells receiveserum free DMEM with 0. 1% BSA only; the positive control cells receivethe ligand but no test compound. Test compounds are prepared in serumfree DMEM with ligand in a 96 well plate, and serially diluted for 7test concentrations.

[2403] 4. After 18 hours of ligand activation, diluted BrdU labelingreagent (1:100 in DMEM, 0.1% BSA) is added and the cells are incubatedwith BrdU (final concentration is 10 μM) for 1.5 hours.

[2404] 5. After incubation with labeling reagent, the medium is removedby decanting and tapping the inverted plate on a paper towel. FixDenatsolution is added (50 μl/well) and the plates are incubated at roomtemperature for 45 minutes on a plate shaker.

[2405] 6. The FixDenat solution is removed by decanting and tapping theinverted plate on a paper towel. Milk is added (5% dehydrated milk inPBS, 200 μl/well) as a blocking solution and the plate is incubated for30 minutes at room temperature on a plate shaker.

[2406] 7. The blocking solution is removed by decanting and the wellsare washed once with PBS. Anti-BrdU-POD solution is added (1:200dilution in PBS, 1% BSA, 50 μl/well) and the plate is incubated for 90minutes at room temperature on a plate shaker.

[2407] 8. The antibody conjugate is removed by decanting and rinsing thewells 5 times with PBS, and the plate is dried by inverting and tappingon a paper towel.

[2408] 9. TMB substrate solution is added (100 μl/well) and incubatedfor 20 minutes at room temperature on a plate shaker until colordevelopment is sufficient for photometric detection.

[2409] 10. The absorbance of the samples are measured at 410 nm (in“dual wavelength” mode with a filter reading at 490 nm, as a referencewavelength) on a Dynatech ELISA plate reader.

[2410] EGF-Induced BrdU Incorporation Assay

[2411] Materials and Reagents:

[2412] 1. Mouse EGF, 201 (Toyobo Co., Ltd., Japan).

[2413] 2. 3T3/EGFRc7.

[2414] Remaining Materials and Reagents and Procedure, as above.

[2415] EGF-Induced Her-2-driven BrdU Incorporation Assay

[2416] Materials and Reagents:

[2417] 1. Mouse EGF, 201 (Toyobo Co., Ltd., Japan).

[2418] 2. 3T3/EGFr/Her2/EGFr (EGFr with a Her-2 kinase domain).

[2419] Remaining Materials and Reagents and Procedure, as above.

[2420] EGF-Induced Her-4-driven BrdU Incorporation Assay

[2421] Materials and Reagents:

[2422] 1. Mouse EGF, 201 (Toyobo Co., Ltd., Japan).

[2423] 2. 3T3/EGFr/Her4/EGFr (EGFr with a Her-4 kinase domain).

[2424] Remaining Materials and Reagents and Procedure, as above.

[2425] PDGF-Induced BrdU Incorporation Assay

[2426] Materials and Reagents:

[2427] 1. Human PDGF B/B (Boehringer Mannheim, Germany).

[2428]2. 3T3/EGFRc7.

[2429] Remaining Materials and Reagents and Procedure, as above.

[2430] FGF-Induced BrdU Incorporation Assay

[2431] Materials and Reagents:

[2432] 1. Human FGF2/bFGF (Gibco BRL, USA).

[2433] 2. 3T3c7/EGFr

[2434] Remaining Materials and Reagents and Procedure, as above.

[2435] IGF1-Induced BrdU Incorporation Assay

[2436] Materials and Reagents:

[2437] 1. Human, recombinant (G511, Promega Corp., USA)

[2438] 2. 3T3/IGF1r.

[2439] Remaining Materials and Reagents and Procedure, as above.

[2440] Insulin-Induced BrdU Incorporation Assay

[2441] Materials and Reagents:

[2442] 1. Insulin, crystalline, bovine, Zinc (13007, Gibco BRL, USA).

[2443] 2. 3T3/H25.

[2444] Remaining Materials and Reagents and Procedure, as above.

[2445] HGF-Induced BrdU Incorporation Assay

[2446] Materials and Reagents:

[2447] 1. Recombinant human HGF (Cat. No. 249-HG, R&D Systems, Inc.USA).

[2448] 2. BxPC-3 cells (ATCC CRL-1687).

[2449] Remaining Materials and Reagents, as above.

[2450] Procedure:

[2451] 1. Cells are seeded at 9000 cells/well in RPMI 10% FBS in a 96well plate. Cells are incubated overnight at 37° C. in 5% CO₂.

[2452] 2. After 24 hours, the cells are washed with PBS, and then areserum starved in 100 μl serum-free medium (RPMI with 0.1% BSA) for 24hours.

[2453] 3. On day 3, 25 μl containing ligand (prepared at 1 μg/ml in RPMIwith 0. 1% BSA; final HGF conc. is 200 ng/ml) and test compounds areadded to the cells. The negative control wells receive 25 μl serum-freeRPMI with 0.1% BSA only; the positive control cells receive the ligand(HGF) but no test compound. Test compounds are prepared at 5 times theirfinal concentration in serum-free RPMI with ligand in a 96 well plate,and serially diluted to give 7 test concentrations. Typically, thehighest final concentration of test compound is 100 μM, and 1:3dilutions are used (i.e. final test compound concentration range is0.137-100 μM).

[2454] 4. After 18 hours of ligand activation, 12.5 μl of diluted BrdUlabeling reagent (1:100 in RPMI, 0.1% BSA) is added to each well and thecells are incubated with BrdU (final concentration is 10 μM) for 1 hour.

[2455] 5. Same as General Procedure.

[2456] 6. Same as General Procedure.

[2457] 7. The blocking solution is removed by decanting and the wellsare washed once with PBS. Anti-BrdU-POD solution (1:100 dilution in PBS,1% BSA) is added (100 μl/well) and the plate is incubated for 90 minutesat room temperature on a plate shaker.

[2458] 8. Same as General Procedure.

[2459] 9. Same as General Procedure.

[2460] 10. Same as General Procedure.

[2461] Exponential BrdU Incorporation Assay

[2462] This assay is used to measure the proliferation (DNA synthesis)of exponentially growing A43 1 cells. The assay will screen forcompounds that inhibit cell cycle progression.

[2463] Materials and Reagents:

[2464] Healthy growing A431 cells. The remainder of the Materials andReagents are the same as listed above in the general protocol section.

[2465] Procedure:

[2466] 1. A431 cells are seeded at 8000 cells/well in 10% FBS, 2 mM Glnin DMEM, on a 96-well plate. Cells are incubated overnight at 37° C. in5% C0₂.

[2467] 2. On day 2, test compounds are serially diluted to 7 testconcentrations in the same growth medium on a 96-well plate and then areadded to the cells on a 96-well tissue culture plate.

[2468] 3. After 20-24 hours of incubation, diluted BrdU labeling reagent(1:100 in DMEM, 0.1% BSA) is added and the cells are incubated with BrdU(final concentration is 10 μM) for 2 hours.

[2469] Steps 5-10 of the General Procedure are used to complete theassay.

[2470] Src Transphosphorylation Assay

[2471] This assay is used to screen for inhibitors of the tyrosinekinase Src.

[2472] Materials and Reagents:

[2473] 1. Coating buffer: PBS containing sodium azide (0.2 mg/ml).

[2474] 2. 1% w/v BSA in PBS.

[2475] 3. Wash buffer: PBS containing 0.05% v/v Tween 20 (PBS-TWEEN)

[2476] 4. 500 mM HEPES pH 7.4.

[2477] 5. ATP (40 μM)+MgCl₂ (80 mM) in distilled water.

[2478] 6. MgCl₂ (80 mM) in distilled water (for no ATP blanks).

[2479] 7. Test compounds, 1 mM in DMSO.

[2480] 8. Assay Buffer: 100 mM HEPES, pH 7.4, containing 2 mM DTT, 0.2mM sodium orthovanadate and 0.2 mgs/ml BSA.

[2481] 9. Partially purified recombinant human Src (UBI (14-117)

[2482] 10. Anti-phosphotyrosine (SUGEN rabbit polyclonal anti-PY).

[2483] 11. HRP-linked goat anti-rabbit Ig (Biosource International#6430)

[2484] 12. HRP substrate ABTS or Pierce Peroxidase substrate.

[2485] 13. Coming ELISA plates.

[2486] Procedure:

[2487] 1. Coat plates with 100 μl of 20 μg/ml poly(Glu-Tyr) (Sigma Cat.

[2488] No. P0275) containing 0.01% sodium azide. Hold overnight at 4° C.

[2489] 2. Block with 1% BSA at 100 μl/well for one hour at roomtemperature.

[2490] 3. Plate test compounds (10 mM in DMSO) at 2 μl/well on a Costarplate ready for dilution with dH₂O and plating to reaction plates.

[2491] 4. Dilute Src kinase 1:10,000 in Reaction Buffer, for 5 platesprepare 25 ml as follows: 2.5mls 1 M HEPES pH 7.4 (stored sterile at 4°C.), 21.85 ml distilled water, 0.1 ml 5% BSA, 0.5 ml 10 mM sodiumorthovanadate (stored sterile at 4° C.), 50 μl 1.OM DTT (stored frozenat −20° C.), and 2.5 μl Src Kinase (stored frozen at −80° C.).

[2492] 5. Add 48 μl of distilled water to the 2 μl of each compound inthe dilution plate then add 25 μl/well of this to the reaction plate.

[2493] 6. Add 50 μl of HRP to each reaction buffer well and then 25 μlATP-MgCl₂/well (MgCl₂ only to no ATP blanks). Incubate at roomtemperature for 15 minutes on plate shaker. Stop reaction by adding 25μl of 0.5 M EDTA to each well.

[2494] 7. Wash 4× with PBS-TWEEN.

[2495] 8. Add 100 μl anti-phosphotyrosine (1:10,000 of anti-pTyr serumor 1:3,000 of 10% glycerol diluted PA-affinity purified antibody) inPBS-TWEEN containing 0.5% BSA, 0.025% Non-fat milk powder and 100 μMsodium orthovanadate. Incubate with continuous shaking at roomtemperature for one hour.

[2496] 9. Wash plates 4× with PBS-TWEEN.

[2497] 10. Add 100 μl HRP-linked Ig (1:5,000) in PBS-TWEEN containing0.5% BSA, 0.025% Non-fat milk powder, 100 μM sodium orthovanadate.

[2498] Incubate with shaking at room temperature for one hour.

[2499] 11. Wash plates 4× with PBS-TWEEN and then once with PBS.

[2500] 12. Develop plate using ABTS or other peroxidase substrate.

[2501] Cell cycle analysis:

[2502] A431 cells in standard growth medium are exposed to a desiredconcentration of a test compound for 20-24 hours at 37 ° C. The cellsare then collected, suspended in PBS, fixed with 70% ice-cold methanoland stained with propidium iodide. The DNA content is then measuredusing a FACScan flow cytometer. Cell cycle phase distribution can thenbe estimated using CelIFIT software (Becton-Dickinson).

[2503] HUV-EC-C Assay

[2504] This assay is used to measure a compound's activity againstPDGF—R, FGF-R, VEGF, aFGF or Flk-1/KDR, all of which are naturallyexpressed by HUV-EC cells.

[2505] DAY 0

[2506] 1. Wash and trypsinize HUV-EC-C cells (human umbilical veinendothelial cells, (American Type Culture Collection, catalogue no. 1730CRL). Wash with Dulbecco's phosphate-buffered saline (D-PBS, obtainedfrom Gibco BRL, catalogue no. 14190-029) 2 times at about 1 ml/10 cm² oftissue culture flask. Trypsinize with 0.05% trypsin-EDTA innon-enzymatic cell dissociation solution (Sigma Chemical Company,catalogue no. C-1544). The 0.05% trypsin is made by diluting 0.25%trypsin/l mM EDTA (Gibco, catalogue no. 25200-049) in the celldissociation solution. Trypsinize with about 1 ml/25-30 cm² of tissueculture flask for about 5 minutes at 37° C. After cells have detachedfrom the flask, add an equal volume of assay medium and transfer to a 50ml sterile centrifuge tube (Fisher Scientific, catalogue no. 05-539-6).

[2507] 2. Wash the cells with about 35 ml assay medium in the 50 mlsterile centrifuge tube by adding the assay medium, centrifuge for 10minutes at approximately 200× g, aspirate the supernatant, and resuspendwith 35 ml D-PBS. Repeat the wash two more times with D-PBS, resuspendthe cells in about 1 ml assay medium/15 cm² of tissue culture flask.Assay medium consists of FI2K medium (Gibco BRL, catalogue no.21127-014) and 0.5% heat-inactivated fetal bovine serum. Count the cellswith a Coulter Counter® (Coulter Electronics, Inc.) and add assay mediumto the cells to obtain a concentration of 0.8-1.0×10⁵ cells/ml.

[2508] 3. Add cells to 96-well flat-bottom plates at 100 μl/well or0.8-1.0×10⁴ cells/well, incubate ˜24th at 37° C., 5% CO₂.

[2509] DAY I

[2510] 1. Make up two-fold test compound titrations in separate 96-wellplates, generally 50 μM on down to 0 μM. Use the same assay medium asmentioned in day 0, step 2 above. Titrations are made by adding 90μl/well of test compound at 200 μM (4× the final well concentration) tothe top well of a particular plate column. Since the stock test compoundis usually 20 mM in DMSO, the 200 μM drug concentration contains 2%DMSO.

[2511] A diluent made up to 2% DMSO in assay medium (F12 K +0.5% fetalbovine serum) is used as diluent for the test compound titrations inorder to dilute the test compound but keep the DMSO concentrationconstant. Add this diluent to the remaining wells in the column at 60μl/well. Take 60 μl from the 120 μl of 200 μM test compound dilution inthe top well of the column and mix with the 60 μl in the second well ofthe column. Take 60 μl from this well and mix with the 60 μl in thethird well of the column, and so on until two-fold titrations arecompleted. When the next-to-the-last well is mixed, take 60 pi of the120 μl in this well and discard it. Leave the last well with 60 pi ofDMSO/media diluent as a non-test compound-containing control. Make 9columns of titrated test compound, enough for triplicate wells each for:(i) VEGF (obtained from Pepro Tech Inc., catalogue no. 100-200, (2)endothelial cell growth factor (ECGF) (also known as acidic fibroblastgrowth factor, or aFGF) (obtained from Boehringer Mannheim Biochemica,catalogue no. 1439 600), or, (3) human PDGF B/B (1276-956, BoehringerMannheim, Germany) and assay media control. ECGF comes as a preparationwith sodium heparin.

[2512] 2. Transfer 50 μl/well of the test compound dilutions to the96-well assay plates containing the 0.8-1.0x10⁴ cells/100 μl/well of theHUV-EC-C cells from day 0 and incubate ˜2 h at 37° C., 5% CO₂.

[2513] 3. In triplicate, add 50 μl/well of 80 μg/ml VEGF, 20 ng/ml ECGF,or media control to each test compound condition. As with the testcompounds, the growth factor concentrations are 4× the desired finalconcentration. Use the assay media from day 0 step 2 to make theconcentrations of growth factors. Incubate approximately 24 hours at 37°C., 5% CO₂. Each well will have 50 μl test compound dilution, 50l]growth factor or media, and 100 [l cells, which calculates to 200μl/well total. Thus the 4× concentrations of test compound and growthfactors become IX once everything has been added to the wells.

[2514] DAY 2

[2515] 1. Add ³H-thymidine (Amersham, catalogue no. TRK-686) at 1μCi/well (10 μl/well of 100 μCi/ml solution made up in RPMI media +10%heat-inactivated fetal bovine serum) and incubate ˜24 h at 37° C., 5%CO₂. RPMI is obtained from Gibco BRL, catalogue no. 11875-051.

[2516] DAY 3

[2517] 1. Freeze plates overnight at −20° C.

[2518] DAY 4

[2519] Thaw plates and harvest with a 96-well plate harvester (TomtecHarvester 96®) onto filter mats (Wallac, catalogue no. 1205-401), readcounts on a Wallac Betaplate™ liquid scintillation counter.

[2520] In Vivo Animal Models

[2521] XENOGRAFT ANIMAL MODELS

[2522] The ability of human tumors to grow as xenografts in athymic mice(e.g., Balb/c, nu/nu) provides a useful in vivo model for studying thebiological response to therapies for human tumors. Since the firstsuccessful xenotransplantation of human tumors into athymic mice,(Rygaard and Povlsen, 1969, Acta Pathol. Microbial. Scand. 77:758-760),many different human tumor cell lines (e.g., mammary, lung,genitourinary, gastro-intestinal, head and neck, glioblastoma, bone, andmalignant melanomas) have been transplanted and successfully grown innude mice. The following assays may be used to determine the level ofactivity, specificity and effect of the different compounds of thepresent invention. Three general types of assays are useful forevaluating compounds: cellular/catalytic, cellular/biological and invivo. The object of the cellular/catalytic assays is to determine theeffect of a compound on the ability of a TK to phosphorylate tyrosineson a known substrate in a cell. The object of the cellular/biologicalassays is to determine the effect of a compound on the biologicalresponse stimulated by a TK in a cell. The object of the in vivo assaysis to determine the effect of a compound in an animal model of aparticular disorder such as cancer.

[2523] Suitable cell lines for subcutaneous xenograft experimentsinclude C6 cells (glioma, ATCC # CCL 107), A375 cells (melanoma, ATCC #CRL 1619), A431 cells (epidermoid carcinoma, ATCC # CRL 1555), Calu 6cells (lung, ATCC # HTB 56), PC3 cells (prostate, ATCC # CRL 1435),SKOV3TP5 cells, S114 (NIH3T3 fibroblast cell line genetically engineeredfor cMet and HGF expressions from NCI), U-87MG (human malignant glioma,ATCC HTB 14) and NIH 3T3 fibroblasts genetically engineered tooverexpress EGFR, PDGFR, IGF-1R or any other test kinase. The followingprotocol can be used to perform xenograft experiments:

[2524] Female athymic mice (BALB/c, nu/nu) are obtained from SimonsenLaboratories (Gilroy, Calif.). All animals are maintained underclean-room conditions in Micro-isolator cages with Alpha-dri bedding.They receive sterile rodent chow and water ad libitum.

[2525] Cell lines are grown in appropriate medium (for example, MEM,DMEM, Ham's F10, or Ham's F12 plus 5% -10% fetal bovine serum (FBS) and2 mM glutamine (GLN)). All cell culture media, glutamine, and fetalbovine serum are purchased from Gibco Life Technologies (Grand Island,N.Y.) unless otherwise specified. All cells are grown in a humidatmosphere of90-95% air and 5-10% CO₂ at 37° C. All cell lines areroutinely subcultured twice a week and are negative for mycoplasma asdetermined by the Mycotect method (Gibco).

[2526] Cells are harvested at or near confluency with 0.05% Trypsin-EDTAand pelleted at 450×g for 10 min. Pellets are resuspended in sterile PBSor media (without FBS) to a particular concentration and the cells areimplanted into the hindflank of the mice (8-10 mice per group, 2-10 ×10⁶cells/animal). Tumor growth is measured over 3 to 6 weeks using veniercalipers. Tumor volumes are calculated as a product of length x width xheight unless otherwise indicated. P values are calculated using theStudents t-test. Test compounds in 50-100 μL excipient (DMSO, orVPD:D5W) can be delivered by IP injection at different concentrationsgenerally starting at day one after implantation.

[2527] TUMOR INVASION MODEL

[2528] The following tumor invasion model has been developed and may beused for the evaluation of therapeutic value and efficacy of thecompounds identified to selectively inhibit KDI/FLK-1 receptor.

[2529] Procedure

[2530] 8 week old nude mice (female) (Simonsen Inc.) are used asexperimental animals. Implantation of tumor cells can be performed in alaminar flow hood. For anesthesia, Xylazine/Ketamine Cocktail (100 mg/kgketamine and 5 mg/kg Xylazine) are administered intraperitoneally. Amidline incision is done to expose the abdominal cavity (approximately1.5 cm in length) to inject 10⁷ tumor cells in a volume of 100 μlmedium. The cells are injected either into the duodenal lobe of thepancreas or under the serosa of the colon. The peritoneum and musclesare closed with a 6-0 silk continuous suture and the skin is closed byusing wound clips. Animals are observed daily.

[2531] Analysis

[2532] After 2-6 weeks, depending on gross observations of the animals,the mice are sacrificed, and the local tumor metastases to variousorgans (lung, liver, brain, stomach, spleen, heart, muscle) are excisedand analyzed (measurement of tumor size, grade of invasion,immunochemistry, in situ hybridization determination, etc.). Additionalassays

[2533] Additional assays which may be used to evaluate the compounds ofthis invention include, without limitation, a bio-flk-1 assay, an EGFreceptor-HER2 chimeric receptor assay in whole cells, a bio-src assay, abio-lck assay and an assay measuring the phosphorylation function ofraf. The protocols for each of these assays may be found in U. S.Application Ser. No. 09/099,842, which is incorporated by reference,including any drawings, herein. Additionally, U.S. Patent No. 5,792,783,filed Jun. 5, 1996 and U.S. Application Serial No. 09/322,297, filed May28, 1999 are incorporated by reference as if fully set forth herein.

[2534] The present invention is not to be limited in scope by theexemplified aspects which are intended as illustrations of singleaspects of the invention, and any clones, DNA or amino acid sequenceswhich are functionally equivalent are within the scope of the invention.Indeed, various modifications of the invention in addition to thosedescribed herein will become apparent to those skilled in the art fromthe foregoing description and accompanying drawings. Such modificationsare intended to fall within the scope of the appended claims.

[2535] All references cited herein are hereby incorporated by referencein their entirety. TABLE 2 Kinase Inhibition of Selected Compounds FGFR1FLK-1 EGFR PDGFR MET FGFR3 SRC P38 Example IC₅₀(μM) IC₅₀(μM) IC₅₀(μM)IC₅₀(μM) IC₅₀(μM) IC₅₀(μM) IC₅₀(μM) IC₅₀(μM) 3 0.031 0.009 >20 0.440.078 1.02 >10 4 0.74 0.074 >20 14.60 0.70 >20 >10 6 0.057 0.021 16.192.95 0.073 4.93 >10 10 1.54 0.18 >20 11.93 0.23 1.82 >10 13 <0.00910.013 13.12 2.32 0.10 0.021 1.05 >10 15 2.07 0.032 >20 10.13 0.37 0.0722.27 4.9 18 1.19 0.42 9.33 10.36 0.27 0.35 7.81 9.5 20 1.15 0.23 >203.39 0.52 1.29 10.38 >10 22 0.057 0.016 15.92 1.64 0.14 0.074 1.58 13.125 0.56 0.18 >20 11.68 0.11 0.34 9.86 >10 27 0.63 0.17 >20 >20 0.15 0.6113.87 >10 29 0.029 0.041 12.88 0.69 0.065 0.32 1.25 >10 32 0.350.051 >20 11.63 0.12 1.77 5.37 >10 34 0.50 1.06 >20 >20 0.13 0.947.26 >10 35 0.22 0.092 >20 1.59 0.34 1.99 9.72 >10 38 0.080 0.029 16.352.19 0.11 0.046 1.25 >10 40 0.19 0.041 >20 11.08 0.27 0.38 6.57 >10 410.56 0.079 >20 3.84 0.32 0.79 5.42 >10 46 0.022 0.009 >20 4.19 0.120.009 0.66 >10 48 0.60 0.012 >20 8.39 1.06 0.19 3.80 >10 52 0.0350.005 >20 1.54 0.092 <0.0091 0.54 >10 53 1.15 0.021 >20 >20 0.29 0.6813.49 >10 57 0.26 0.029 >20 >20 0.42 0.087 4.74 >10 58 0.25 0.054 >2016.06 0.073 0.22 4.81 >10 60 0.15 0.018 7.01 2.37 0.25 0.55 2.01 7.9 610.021 0.006 >20 9.12 0.11 <0.0091 1.72 6.3 63 0.24 0.043 14.98 2.180.043 0.094 1.14 93 0.083 <0.0091 >20 3.76 0.08 >20 99 0.61 0.17 >20 >200.18 >20 104 0.3 0.066 >20 18.97 0.58 7.09 119 0.24 0.18 >20 9.87 0.0598.61 140 0.52 0.075 >20 >20 0.68 4.31

[2536] Table 2 shows data of kinase inhibition of selected compounds.The Example numbers of Table 2 correspond to the Example numbers inTable 1 of the specification.

[2537] Scatter Assay

[2538] Materials and Reagents:

[2539] 1. HGF: recombinant human HGF, Cat. No. 249-HG, R&D Systems,Inc., USA. HGF is dissolved in PBS with 0.1% BSA at a stockconcentration of 50 mg/ml.

[2540] Procedure:

[2541] 2. cell lineL MDCK clone #2.

[2542] 3. MDCK cell were plated in 96-well plate in MEM with 10% FBS atlow density of 25 cells/well and grown to small colonies of 10-15 cells.

[2543] 4. Cells were then treated with HGF (50 ng/Ml) in the presence ofvarious concentrations of compounds diluted in MEM with 0.5% FBS.

[2544] 5. After overnight incubation, cells were fixed and stained with0.2% crystal violet in 10% buffer Formalin.

[2545] 6. Plates were allowed to air dry.

[2546] 7. Photographs were taken of individual colonies.

[2547] Met Phosphorylation—Cellular Assay

[2548] Materials and Reagents:

[2549] 1. Falcon 10 cm culture dishes.

[2550] 2. A549 lung carcinoma cells.

[2551] 3. F12K growth medium (with 2% FBS +2 mM glutamine.

[2552] 4. F12K assay medium (with 0.1% BSA).

[2553] 5. Fisher cell scrapers.

[2554] 6. Lysis buffer (HNTG, 1 mM sodium orthovanidate, 1 mM PMSF and 2mM sodium fluoride).

[2555] 7. 1.5 ml Eppendorf tubes.

[2556] 8. Eppendorf microcentrifuge.

[2557] 9. BCA assay reagents A and B (#23223 and 23224, Pierce).

[2558] 10. Sample tube rotator.

[2559] 11. Gel blot container rotator.

[2560] 12. 5× sample buffer.

[2561] 13. Novex pre-cast tris-glycine 8% acrylamide gels.

[2562] 14. Bio-Rad electrophoresis chamber.

[2563] 15. SDS-PAGE buffer.

[2564] 16. TBS (pH 7.6) +0.1% Triton X-100 (TBST), with and wihtout 5%milk.

[2565] 17. Western blot transfer buffer.

[2566] 18. Osmonics nitrocellulose paper.

[2567] 19. Bio—Rad Transblot paper.

[2568] 20. Gel transfer apparatus.

[2569] 21. Anti-phosphotyrosine (mouse monoclonal).

[2570] 22. Bio—Rad Kaleidoscope Prestained Standards (161-0324).

[2571] 23. Anti-h-met (C-28) rabbit polyclonal, conjugated andnon-conjugated with agarose (#sc-161 AC and sc-161, Santa CruzBiotechnology, Inc.).

[2572] 24. Donkey and anti-rabbit Ig-HRP (NA 934, Amersham).

[2573] 25. Sheet anti-mouseIg-HRP (NA 931, Amersham).

[2574] 26. SuperSignal West Pico Chemiluminescent Substrate (#34080,Pierce).

[2575] 27. Saran Wrap.

[2576] 28. Kodak BioMax exposure cassette.

[2577] 29. Fuji X-ray film.

[2578] 30. Kodak film developer.

[2579] Precedure:

[2580] 1. Plate cells in 10 cm dishes with growth medium with 2% FBS+2mM glutamine. Grow to near confluency.

[2581] 2. Serum starve cells overnight in assay medium with 0.1 % BSA.

[2582] 3. Add drug to the plates, one dose per plate, usually in a2-flod titration. Add asay medium (with the same DMSO concentration asthe drugs) for no drug.

[2583] 4. Incubate plates 4-5 hours with the drug, then add HG, 50 ng/mlfor 10 minutes.

[2584] 5. Wash plates once with PBS, add 400 μl lysis buffer, and scrapeoff the cells. Collect in 1.5 ml Eppendorf tubes.

[2585] 6. After about 10-20 minutes in the lysis buffer, centrifugelysates in a microcentrifuger at full speed (14,000g) and collect thesupernatants in a separate Eppendorf tube.

[2586] 7. Determine protein concentration with the BCA assay reagents.

[2587] 8. Adjust sample concentration to 0.5 mg protein in 0.4 ml usinglysis buffer.

[2588] 9. Add 15 μl anti-h-met AC for immunoprecipitation, rotatesamples for 2 hours at 4° C.

[2589] 10. Wash samples 3 times with lysis buffer and resuspend in 35 μl5× sample buffer.

[2590] 11. Boil sample at 100° C. for 10 minutes and microcentrifuge athighest setting for 30 minutes to pellet the agarose beads.

[2591] 12. Load 15 μl each to 2 gels, one for anti-phosphorylation andthe other for anti-h-met. Also load 10 μl of prestained standards, onelane per gel.

[2592] 13. Run gel around 100-125 V, then transfer gel to nitrocelluloseeither overnight at 70 mAmps or I hour at 500 mAmps.

[2593] 14. Block membranes on rotator for 1 hour in TBS +0.1% TritonX-100 (TBST)+5% PBS. All steps from this point are at room temperatureunless otherwise unless otherwise noted.

[2594] 15. Add 0.8 μg/ml antiphosphotyrosine and 0.25 μg/ml anti-h-meton rotator either for 2 hours or overnight.

[2595] 16. Wash membranes 3 times 5 minutes each in TBST on rotator.

[2596] 17. Add HRP-conjugated antibodies )sheep anti-mouse for theantiphosphotyroeins; donkey anti-rabbit for the nati-h-met) at 1:5000for approximately 45 minutes on rotator.

[2597] 18. Wash membranes 3 times for 5 minutes each in TBST on rotator.

[2598] 19. Add the 2 reagents in th3e SuperSignal kit together in equalvolumes (3 ml+3 ml for each blot), rotate for 1-2 minutes.

[2599] 20. Wrap blots in Saran Wrap and tape securely inside theexposure cassette.

[2600] 21. In the darkroom with only the safety light on, place a sheetof film inside the cassette. After an allotted time, remove film andplace in the developer machine for automatic processing. Experiment withthe exposure time to get proper exposure.

What is claimed is:
 1. A compound of the formula I:

wherein: R¹ is an aryl or heteroaryl substituent, optionally substitutedby one or more substituent selected from the group consisting ofhalogen, —OR⁶, —COR⁶, —COOR⁶, OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷, —CN,—NO₂, —CX₃, —SR⁶, SOR⁶, —SO₂R⁶, —SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷,perfluoroalkyl, lower alkyl, lower alkyl further substituted by one ormore of R², lower alkenyl, lower alkenyl further substituted by one ormore of R², lower alkynyl, lower alkynyl further substituted by one ormore of R², cycloalkyl, cyeloalkyl further substituted by one or more ofR², a heterocyclic ring, a hetero cyclic ring further substituted by oneor more of Ra, aryl and aryl further substituted by one or more of R²;R² is selected from the group consisting of hydrogen, halogen, —OR⁶,—COR⁶, —COOR⁶, OCOR⁶, —CONR⁶R⁷, —R⁶COR⁷, —NR⁶R⁷, —CN, —NO₂, —CX₃, —SR⁶,SOR⁶, —SO₂R⁶, —SO₂O⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷, perfluoroalkyl, lower alkyl,lower alkenyl, lower alkynyl, eycloalkyl, a heterocyclic ring and aryl;R³ is selected from the group consisting of hydrogen, halogen, —OR⁶,—COR⁶, —COOR, OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷, —CN, —NO₂, —CX₃, —SR⁶,SOR⁶, —SO₂R⁶, —SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷, perfluoroalkyl, loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, a heterocyclic ring, aheterocyclic ring further substituted by one or more of R² and aryl,wherein said lower alkyl is further substituted by —CONR⁶R⁷, NR⁶R⁷,—SO₂R⁶, —R⁶NSO₂R, or SO₂NR⁶R⁷; R⁴ is selected from the group consistingof hydrogen, halogen, —OR⁶, —COR⁶, —COOR⁶, —OCOR⁶, —CONR⁶ R⁷, —R⁶NCOR⁷,—NR⁶R⁷ , —CN, —NO₂, —CX₃, —SR⁶, SOR⁶, —SO₂R⁶, —SO₂OR⁶, —SO₂NR⁶R⁷,—R⁶NSO₂R⁷, perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, a heterocyclic ring and aryl, wherein said lower alkyl isfurther substituted by —CONR⁶R⁷, NR⁶R⁷, —SO₂R⁶, —R⁶NSO₂R, or SO₂NR⁶R⁷;R⁵ is selected from the group consisting of hydrogen, halogen, —OR⁶,—COR⁶, —COOR⁶, OCOR⁶, —CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷, —CN, —NO₂, —CX₃, —SR⁶,SOR⁶, —SO₂R⁶, —SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷, perfluoroalkyl, loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, a heterocyclic ring andaryl; provided that no more than one of R³, R⁴, or R⁵is hydrogen; R³ andR⁴ or R⁴ and R⁵ may be linked together to form a 4-, 5-, 6- or7-membered ring optionally containing one or more hetero atoms selectedfrom the group consisting of O, N, S, SO and SO₂, which may contain 1 or2 double bonds and may be further substituted by one or more of—(CH₂)_(n)—NR⁶R⁷,—(CH₂)_(n)—CR⁶R⁷, —(CH₂)_(n)—C(O)—(CH₂)_(n)—NR⁶R⁷,—(CH₂)_(n)SO₂R⁶R⁷, —(CH₂)_(n)NSO₂R⁶R⁷ or —(CH₂)_(n)—C(O)—R⁶ wherein n is0-4; R⁶ and R⁷ are independently selected from the group consisting ofhydrogen, —CX₃, perfluoroalkyl, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, a heterocyclic ring and aryl; wherein lower alkyl,lower alkenyl, lower alkynyl, cycloalkyl, the heteocyclic ring or arylmay be further substituted by one or more of (i) —NR¹²R¹³, (ii) hydroxy,(iii) halo, (iv) a heterocyclic ring, (v) lower alkyl, (vi)—C(O)NR¹²R¹³, (vii) —OR¹², (viii) —SO₂R¹²R¹³, or (ix) —COR⁶; whereinsaid heterocyclic ring (iv) may be further substituted by one or more oflower alkyl, —COR¹², —NR¹²COR¹³, halogen, —OR¹², CX₃, —C(O)NR¹²R¹³,—SO₂R¹²R¹³, or —SO₂NR¹²R¹³, or R⁶ and R⁷ may be linked together to forma 4, 5- or 6-membered ring, optionally containing a hetero atom selectedfrom the group consisting of N, O, S and SO₂, which may be furthersubstituted by —CONR¹²R¹³, lower alkyl, hydroxy, —(CH₂)_(n)—NR¹²R¹³,—CH₂)_(n)-heterocycle, —(CH₂)_(n)—C(O)—NR¹²R¹³, —(CH₂)_(n)SO₂R¹²R¹³, or—(CH₂)_(n)NSO₂R¹²R¹³, wherein said heterocycle may be furthersubstituted by halo, lower alkyl, —COR¹², hydroxy, —C(O)NR¹²R¹³, —OR¹²,—SO₂R¹² R¹³, or —SO₂NR¹²R¹³; X is fluorine, chlorine, bromine or iodine;R¹² is selected from the group consisting of hydrogen, —CX₃,perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl,—(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)-heterocycle, and aryl; R¹³ is selectedfrom the group consisting of hydrogen, —CX₃, perfluoroalkyl, loweralkyl, lower alkenyl, lower alkynyl, —(CH₂)_(n)-cycloalkyl,—(CH₂)_(n)-heterocycle, and aryl; or R¹² and R¹³ may be linked togetherto form a 4-, 5- or 6-membered ring optionally containing one or morehetero atoms selected from the group consisting of O, N, S, SO and SO₂,which may contain 1 or 2 double bonds; or a pharmaceutically acceptablesalt thereof.
 2. The compound of claim 1, wherein R³ and R⁴ or R⁴ and R⁵may be linked together to form a ring.
 3. The compound of claim 2,wherein the R³ and R⁴ or R⁴ and R⁵ are linked together to form a ring,the ring together with pyrrole is selected from the group consisting of:


4. The compound of claim 1, wherein said compound is selected from thegroup consisting of:2-methyl-4-[3-(4-methyl-piperazin-1-yl-propyl]-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylicacid ester,3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one,2,4-dimethyl-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,4-(4-fluoro-phenyl)-3-[5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one,2-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,3-[3-(3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-[3-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-[3-((S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one,5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3 ]triazol-1-yl-ethyl)-amide,3-[3-(3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-[3-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-[3-((S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one,5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylicacid ethyl ester,3-[3-(cis-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-[3-(trans-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one,4-(4-chloro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,4-(4-chloro-phenyl)-3-[3-(3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-chloro-phenyl)-3-[3-(3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylicacid ethyl ester,4-(4-chloro-phenyl)-3-[3-(cis-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-chloro-phenyl)-3-[3-(trans-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(3-chloro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,4-(3-chloro-phenyl)-3-[3-(3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(3-chloro-phenyl)-3-[3-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(3-chloro-phenyl)-3-[3-((S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,2-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemnethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,4-(3-chloro-phenyl)-3-[3-(cis-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(3-chloro-phenyl)-3-[3-(trans-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,3-[4-(cis-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-[4-(trans-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,2-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,2-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,3-[3-(3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-[3-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-I,3-dihydro-indol-2-one,3-[3-((S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,3-[4-(cis-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-[4-(trans-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,2-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,2-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diisopropylamino-ethyl)-amide,4-(4-bromo-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[ 1,2,3]triazol-1-yl-ethyl)-amide,4-(4-bromo-phenyl)-3-[4-(cis-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-bromo-phenyl)-3-[4-(trans-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,2-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,2-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diisopropylamino-ethyl)-amide,5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,4-(3-Bromo-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,3-[4-(cis-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one,3-[4-(trans-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one,2-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,2-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diisopropylamino-ethyl)-amide,5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethyiamino-ethyl)-amide,5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-dimethyl-1H-pyrro1-2-ylmethylene)-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide,5-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,3-[3,5-Dimethyl-4-(4-methyl-[piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one,5-[4-(2-Fluoro-phenyl)-2-oxo-1,²-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,2-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,2-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,2-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,3-[3-(cis-3,5-dimethyl-piperazine-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-[3-(trans-3,5-dimethyl-piperazine-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one,5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (3-diethylamino-propyl)-amide,2-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide,5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (3-diethylamino-propyl)-amide,3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one,2,4-Dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,2,4-Dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,2,4-Dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethy]-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,3-{3-[cis-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene}-4-(2-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one,2,4-Dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-diethylamino-propyl)-amide,5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide,3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one,3-{3-Methyl-4-[cis-3,5-dimethyl-piperazine-1-carbonyl]-1H-pyrrol-2-ylmethylene}-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one,4-(3-chloro-4-fluoro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,5-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide,4-(4-chloro-phenyl)-3-{3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-ylmethylene}-1,3-dihydro-indol-2-one,4-(2-fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-chloro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(3-bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(3-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one,3-{4-[cis-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,4-(4-Chloro-phenyl)-3-{4-[cis-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-Bromo-phenyl)-3-{4-[cis-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,3-{4-[cis-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-{4-[cis-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-{4-[cis-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-phenyl-1,3-dihydro-indol-2-one,4-(4-chloro-phenyl)-3-{4-{3-[cis-3,5-dimethyl-piperazin-1-yl]-3-oxo-propyl}-3,5-dimethyl-1H-pyrrol-2-ylmethylene}-1,3-dihydro-indol-2-one,3-{4-{3-[cis-3,5-Dimethyl-piperazin-1-yl]-3-oxo-propyl}-3,5-dimethyl-1H-pyrrol-2-ylmethylene}-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one,2,4-Dimethyl-5-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-diethylarnino-ethyl)-amide,2,4-Dimethyl-5-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amnide,5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amnide,5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide,3-[3-(trans-3,5-Dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one,4-(4-Chloro-phenyl)-3-[3-(trans-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(3-Chloro-phenyl)-3-[3-(trans-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,3-[4-(trans-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-[4-(trans-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,4-(4-Bromo-phenyl)-3-[4-[trans-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,3-[4-(trans-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-bromo-phenyl)-i,3-dihydro-indol-2-one,3-{3-[trans-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene}-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-{3-[trans-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene}-4-(2-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one,3-{3-Methyl-4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-l1H-pyrrol-2-ylmethylene}-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one,3-{4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,4-(4-Chloro-phenyl)-3-{4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-Bromo-phenyl)-3-{4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,3-{4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene-4-(4-methoxy-phenyl)-I,3-dihydro-indol-2-one,3-{4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-{4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-phenyl)-1,3-dihydro-indol-2-one,4-(4-chloro-phenyl)-3-{4-f{3-[trans-3,5-dimethyl-piperazin-1I-yl]-3-oxo-propyl)}-3,5-dimethyl-1H-pyrrol-2-ylmethylene}-1,3-dihydro-indol-2-one, 3-{ 4-{3-[trans-3,5-Dimethyl-piperazin-1-yl]-3-oxo-propyl-3,5-dimethyl-1H-pyrrol-2-ylmethylene}-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,2-Methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylicacid ethyl ester,3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrro1-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one,2,4-Dimethyl-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,3-[3,5-Dimethyl-4-(4-methyl-pilferazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,4-(4-Fluoro-phenyl)-3-[5-methyl-3-(4-methylpiperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,2-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl) amide,3-[3-((S)-3-Dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-yhnethylene]-4-(4-fluoro-phenyl)-1,3-dihydroindol-2-one,3-[3-((R)-3-Dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydroindol-2-one,3-[3,5-Dimethyl-4-(4-methyl-.piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one,5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,3-[3-((S)-3-Dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydroindol-2-one,3-[3-((R)-3-Dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydroindol-2-one,5-[4-(3-Fluoro-pheny])-2-oxo-1,2-dihydro-indol-3-ylideinemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylicacid ethyl ester,3-[3-(cis-3,5-Dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydroindol-2-one,4-(4-Chloro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,5-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,4-(4-Chloro-phenyl)-3-[3-((S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-Chloro-phenyl)-3-[3-((R)-3-dimethylamino-pyrrolidme-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,5-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylicacid ethyl ester,4-(4-Chloro-phenyl)-3-[3-(cis-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2ylmethylene]-I,3-dihydro-indol-2-one,4-(3-Chloro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,5-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,4-(3-Chloro-phenyl)-3-[3-((S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(3-Chloro-phenyl)-3-[3-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,2-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,4-(3-Chloro-phenyl)-3-[3-(cis-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2ylmethylene]-1,3-dihydro-indol-2-one,3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,5-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethy]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,3-[4-(cis-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,2-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,2-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,3-[3-((S)-3-Dimethylamino˜pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-[3-((R)-3-Dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,3-[4-(cis-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,2-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,2-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diisopropylamino-ethyl)-amide,4-(4-Bromo-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indo1-2-one,5-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[I,2,3]triazol-1-yl-ethyl)-amide,4-(4-Bromo-phenyl)-3-[4-[cis-3,5-dimethyl-.piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indo1-2-one,2-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,2-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-El,2,3]triazol-1-yl-ethyl)-amide,5-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diisopropylamino-ethyl)-amide,5-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one,5-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,3-[4-(cis-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one,2-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,2-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,5-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diisopropylamino-ethyl)-amide,5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylicacid (2-diethylamino-ethyl)-amide,3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4(3-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4(4-chioro-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4(3-chloro-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4(4-bromo-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4(3-bromo-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dlhydroindol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide,3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(2-fluoro-phenyl)-1,3-dlhydro-indol-2-one,5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dlhydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-anide,5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dlhydro-indol-3-ylideneniethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-anTlide,5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dlhydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,2-[4-(2-fluoro-phenyi)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dlhydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl) amide,3-[3-(cis-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(2-fluoro-phenyl)-1,3-dihydroindol-2-one,5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (3-diethylamino-propyl)-amide,2-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide,5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (3-diethylamino-propyl)-amide,3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one,2,4-Dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyn-ole-3-carboxylicacid (2-diethylamino-ethyl)-amide,2,4-LMmethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-aniide,2,4-Dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol-1-yl-ethyl)-amide,5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide,5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-[l,2,3]triazol-1-yl-ethyl)-amide,3-[3-(cis-3,5-dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(2-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one2,4-Dimethyl-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-diethylamino-propvl)-amide, 2,4-Dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-diethylamino-propyl)-amide,5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide,3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4(3-trifluoromethyl-phenyl)-1,3-dihydro indol-2-one,3-[3-Methyl-4-(cis-3,5-dimethyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one,4-(3-chloro-4-fluoro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,5-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid(2-diethylamino-ethyl)-amide,5-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid(2-[l,2,3]triazol-1-yl-ethyl)-amide,2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylicacid(2-pyrrolidin-1-yl-ethyl)-amide,2-[4-(3-.chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1Npyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide,2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1Hpyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide,4-(4-chloro-phenyl)-3-[3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(2-fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-chloro-phenyl)-3-[3-methyl-4-.(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(3-bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(3-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one,3-[4-(cis-3,5-dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydroindol-2-one,4-(4-Chloro-phenyl)-3-[4-[cis-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2ylmethylene]-1,3-dihydro-indol-2-one,4-(4-Bromo-phenyl)-3-[4-(cis-3,5-dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrol-2ylmethylene]-1,3-dihydro-indol-2-one,3-[4-(cis-3,5-dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrol-2-ylmethylene-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-[4-(cis-3,5-dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-[4-(cis-3,5-dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one,4-(4-chloro-phenyl)-3-[4-[3-(cis-3,5-dimethyl-piperazin-1-yl)-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,3-[4-[3-(cis-3,5-Dimethyl-piperazin-1-yl)-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2one,2,4-Dimethyl-5-[2-oxo-4-(4-trifluoromethoxyphenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,2,4-Dimethyl-5-[2-oxo-4-(4-trifluoromethoxyphenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid(2-[I,2,3]triazol 1-yl-ethyl)-amide,5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-.pyrrolidin-1-yl-ethyl)-amide,5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (2-[1,2,3]triazol 1-yl-ethyl)-amide,5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide,3-[3-(trans-3,5-Dimethyl-piperazine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydroindo l-2-one, 4-(4-Chloro-phenyl)-3-[3-(trans-3,5-dimethylpiperazine-1-carbonyl)-5-methyl-1H-pyrrol-2ylmethylene]-1,3-dihydro-indol-2-one,4-(3-Chloro-phenyl)-3-[3-(trans-3,5-dimethylpiperazine-1-carbonyl)-5-methyl-1H-pyrrol-2ylmethylene]-1,3-dihydro-indol-2-one,3-[4-(trans-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-[4-(trans-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,4-(4-Bromo-phenyl)-3-[4-[trans-3,5-dimethylpiperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,3-[4-(trans-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one,3-[3-[trans-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one,3-[3-[trans-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-IN-pyrrol-2-ylmethylene]-4-(2-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one,3-[3-Methyl-4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indo1-2-one, 3-[4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1N-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one,4-(4-Chloro-phenyl)-3-[4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,4-(4-Bromo-phenyl)-3-[4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one,3-[4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-[4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one,3-{4-[trans-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one,4-(4-chloro-phenyl)-3-(4-[3-[trans-3,5-dimethyl-piperazin-1-yl]-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-oneand3-(4-[3-[trans-3,5-Dimethyl-piperazin-1-yl]-3-oxo-propyl]-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one.5. A method of modulating the catalytic activity of a protein kinasecomprising contacting said protein kinase with a compound of claim 1, ora pharmaceutically acceptable salt thereof
 6. The method of claim 5,wherein said protein kinase is selected from the group consisting of areceptor tyrosine kinase, a non-receptor tyro sine kinase and aserine-threonine kinase.
 7. The method of claim 6, wherein said receptortyrosine kinase whose catalytic activity is modulated by a compound ofthis invention is selected from the group consisting of EGF, HER2, HER3,HER4, IR, IGF-1R, IRR, PDGFRα, PDGFRβ, CSFIR, C-Kit, C-fms, Flk-1R,Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R, FGFR-4R, DDR-1, DDR-2and Met.
 8. The method of claim 6, wherein said cellular tyrosine kinasewhose catalytic activity is modulated by a compound of this invention isselected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70,Fes/Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, Aur 2 andYrk.
 9. The method of claim 6, wherein said serine-threonine proteinkinase whose catalytic activity is modulated by a compound of thisinvention is selected from the group consisting of CDK2, Raf, NEK andBUB
 1. 10. A method for treating a protein kinase related disordercomprising administering to an organism in need thereof atherapeutically effective amount of a compound of claim 1, orpharmaceutically acceptable salt thereof.
 11. The method of claim 10,wherein said protein kinase related disorder is selected from the groupconsisting of a receptor tyrosine kinase related disorder, a non-receptor tyrosine kinase disorder and a serine-threonine kinase relateddisorder.
 12. The method of claim 10, wherein said protein kinaserelated disorder is selected from the group consisting of a MET kinaserelated disorder, FLK kinase related disorder, a FGFR kinase relateddisorder, SRC kinase related disorder, a DDR kinase related disorder,and a PDGFR kinase related disorder.
 13. The method of claim 10, whereinsaid protein kinase related disorder is a cancer.
 14. The method ofclaim 13, wherein said cancer is selected from the group consisting ofsquamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma,lung cancer, bladder cancer, head and neck cancer, melanoma, ovariancancer, prostate cancer, breast cancer, small-cell lung cancer, glioma,colorectal cancer, genitourinary cancer and gastrointestinal cancer. 15.The method of claim 10, wherein said protein kinase related disorder isselected from the group consisting of diabetes, an autoimmune disorder,a hyperproliferation disorder, restenosis, fibrosis, psoriasis, vonHeppel-Lindau disease, osteoarthritis, rheumatoid arthritis,angiogenesis, an inflammatory disorder, an immunological disorder and acardiovascular disorder.
 16. The method of claim 10, wherein saidorganism is a human.
 17. A pharmaceutical composition comprising acompound of claim 1 or a pharmaceutically acceptable salt thereof. 18.The pharmaceutical composition of claim 17, which further comprises aphysiologically acceptable carrier or excipient.
 19. The pharmaceuticalcomposition of claim 17, which further comprises other therapeuticagents.
 20. The pharmaceutical composition of claim 19, wherein theother therapeutic agent is selected from the group consisting of analkylating agent, an antimetabolic chemotherapeutic agent, a naturalproduct based chemotherapeutic agent, mitoxantrone or paclitaxel.
 21. Acompound of formula II:

wherein each R⁸ is independently halogen, —OR⁶, —COR⁶, —COOR⁶, OCOR⁶,—CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷, —CN, —NO₂, —CX₃, —SR⁶, SOR⁶, —SO₂R⁶,—SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷, perfluoroalkyl, lower alkyl, lower alkylfurther substituted by one or more of R², lower alkenyl, lower alkenylfurther substituted by one or more of R², lower alkynyl, lower alkynylfurther substituted by one or more of R², cycloalkyl, cycloalkyl furthersubstituted by one or more of R², a heterocyclic ring, a heterocylicring further substituted by one or more of R², aryl and aryl furthersubstituted by one or more of R²; R² is selected from the groupconsisting of hydrogen, halogen, —OR⁶, —COR⁶, —COOR⁶, OCOR⁶, —CONR⁶R⁷,—R¹²NCR¹³, —NR⁶R⁷, —R⁶NC(O)R⁷, —CN, —NO₂, —CX₃, —SR⁶, SOR⁶,—SO₂R⁶,—SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷, perfluoroalkyl, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, a heterocyclic ring and aryl; R⁶ andR⁷ are independently selected from the group consisting of hydrogen,—CX₃, perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, a heterocyclic ring and aryl; wherein lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, the heteocyclic ring or aryl may befurther substituted by one or more of (i) —NR¹²R¹³, (ii) hydroxy, (iii)halo, (iv) a heterocyclic ring, (v) lower alkyl, (vi) —C(O)—NR¹²R¹³,(vii) —OR¹², (viii) —SO₂R¹²R¹³, or (ix) —COR⁶; wherein said heterocyclicring (iv) may be further substituted by one or more of lower alkyl,—COR¹², —NR¹²COR¹³, halogen, —OR¹², CX₃, —C(O)NR¹²R¹³, —SO₂R¹²R¹³ or—SO₂NR¹²R¹³, or R⁶ and R⁷ may be linked together to form a 4-, 5- or6-membered ring, optionally containing a hetero atom selected from thegroup consisting of N, O, S and SO, which may be further substituted by—CONR¹²R¹³, lower alkyl, hydroxy, —(CH₂)_(n)—NR¹²R¹³,CH₂)_(n)-heterocycle, —(CH₂), —C(O)—NR¹²R¹³, —(CH₂)_(n)SO₂R¹²R¹³, or—(CH₂),NSO₂R¹²R¹³, wherein said heterocycle may be further substitutedby halo, lower alkyl, —COR¹², hydroxy, —C(O)—NR¹²R¹³, —OR¹², —SO₂R¹²R¹³,or —SO₂NR¹²R¹³; X is fluorine, chlorine, bromine or iodine; R¹² isselected from the group consisting of hydrogen, —CX₃, perfluoroalkyl,lower alkyl, lower alkenyl, lower alkynyl, —(CH₂)_(n)-cycloalkyl,—(CH₂)_(n)-heterocycle, and aryl; R¹³ is selected from the groupconsisting of hydrogen, —CX₃, perfluoroalkyl, lower alkyl, loweralkenyl, lower alkynyl, —(CH₂),-cycloalkyl, —(CH₂)_(n)-heterocycle, andaryl; or R¹² and R¹³ may be linked together to form a 4-, 5- or6-membered ring optionally containing one or more hetero atoms selectedfrom the group consisting of O, N, S, SO and SO₂, which may contain 1 or2 double bonds and may be further substituted by halogen, —OR⁶, —COR⁶,—COOR⁶, OCOR⁶, —CONR⁶R⁷, —R¹²NCOR¹³, —NR⁶R⁷, —R⁶NC(O)R⁷ , —CN, —NO₂,—CX₃, —SR⁶, SOR⁶, —SO₂R⁶,—SO₂OR⁶, —SO₂NR⁶R⁷, —R⁶NSO₂R⁷, perfluoroalkyl,lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, a heterocyclicring and aryl; R⁹ is selected from the group consisting of halogen,—CX₃, lower alkyl, cycloalkyl, a heterocyclic ring and aryl, each ofwhich may be further substituted by halogen, —OR⁶, —COOR⁶, —OCOR⁶,—CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷ , —CX₃, —SR⁶, SOR⁶, SO₂R⁶, —SO₂OR⁶,SO₂NR⁶R^(7,) or —R⁶NSO₂R⁷; and m is 1 or 2, or a pharmaceuticallyacceptable salt thereof.
 22. A compound of claim 21 wherein R⁸ ishydrogen, halogen, lower alkyl or lower alkyl substituted with R²; R² ishydroxy or hydrogen; n is 0-2; R⁹ is lower alkyl; m is 1 or 2; R⁶ and R⁷independently are lower alkyl which may be substituted with hydrogen,hydroxy or NR¹²R¹³ R⁶ and R⁷ can form a 5 or 6 membered ring with one ormore hetero atoms selected from N, O which is further substituted withlower alkyl or —(CH₂)_(n)NR¹²R¹³; R¹² and R¹³ independently arehydrogen, lower alkyl, —C(O)-lower alkyl, or —(CH₂)_(n)-cycloalkyl; orR¹² and R¹³ can form a 5 or 6 membered ring having one or more heteroatoms selected from the group consisting of O and N and having 1 or 2double bonds wherein the ring is further substituted with hydroxy,—C(O)-lower alkyl or —NR⁶C(O)-lower alkyl.
 23. A compound of formulaIII:

wherein each R⁸ is independently halogen, —OR⁶, —COR⁶, —COOR⁶, OCOR⁶,—CONR⁶R⁷, —R⁶NCOR⁷, —NR⁶R⁷, —CN, —NO₂, —CX₃, —SR⁶, —SO₂R⁶, —SO₂OR⁶,—SO₂NR⁶R⁷, —R⁶NSO₂R⁷, perfluoroalkyl, lower alkyl, lower alkyl furthersubstituted by one or more of R², lower alkenyl, lower alkenyl furthersubstituted by one or more of R², lower alkynyl, lower alkynyl furthersubstituted by one or more of R², cycloalkyl, cycloalkyl furthersubstituted by one or more of R², a heterocyclic ring, a heterocyclicring further substituted by one or more of R², aryl and aryl furthersubstituted by one or more of R²; R² is selected from the groupconsisting of hydrogen, halogen, —OR⁶, —COR⁶, —COOR⁶, OCOR⁶, —CONR⁶R⁷,—R⁶NCOR⁷, —NR⁶R⁷, —CN, —NO₂, —CX₃, —SO₂R⁶, —SO₂OR⁶, —SO₂NR⁶R⁷, —RNSO₂R⁷,perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aheterocyclic ring and aryl; R⁶ and R⁷ are independently selected fromthe group consisting of hydrogen, —CX₃, perfluoroalkyl, lower alkyl,lower alkenyl, lower alkynyl, cycloalkyl, a heterocyclic ring and aryl;wherein lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, theheteocyclic ring or aryl may be further substituted by one or moreof—NR¹²R¹³, hydroxy, halo, a heterocyclic ring, lower alkyl,—C(O)—NR²R¹³, —OR¹², or —SO₂R¹²R¹³; wherein said a heterocyclic ring maybe further substituted by one or more of lower alkyl, —COR¹²,—NR¹²COR¹³, halogen, —OR¹², CX₃, —C(O)NR¹²R¹³, —SO₂R¹²R¹³, or—SO₂NR¹²R¹³, or R⁶ and R⁷ may be linked together to form a 4, 5- or6-membered ring, optionally containing a hetero atom selected from thegroup consisting of N, O, S, SO and SO₂, which may be furthersubstituted by CONR¹²R¹³, lower alkyl, hydroxy, —(CH₂)_(n)—NR¹²R¹³,—(CH₂)_(n)-heterocycle, —(CH₂)_(n)—C(O)—NR¹²R¹³, —(CH₂)_(n)SO₂R¹²R¹³, or—(CH₂)_(n)NSO₂R¹²R¹³, wherein said heterocycle may be furthersubstituted by lower alkyl, —COR¹², hydroxy, —C(O)—NR¹²R¹³,—OR¹²,—SO₂R¹²R¹³, or —SO₂NR¹²R¹³; X is fluorine, chlorine, bromine or iodine;R¹⁰ is H, lower alkyl, lower alkyl substituted with one or more of R²,—(CH₂)_(n)NR⁶R⁷, —CONR⁶R⁷, —SO₂NR⁶R⁷, —(CH₂)_(n)—SR⁶, —(CH₂)_(n)—SOR⁶,—(CH₂)_(n)—SO₂R⁶, —(CH₂)_(n)—SO₂NR⁶R⁷, or —(CH₂)_(n)-OR⁶; R¹¹ is H,lower alkyl, lower alkyl substituted with one or more ofR²,—(CH₂)_(n)NR⁶R⁷, —CONR⁶R⁷, —SO₂NR⁶R⁷, —(CH₂)_(n)—SR⁶,—(CH₂)_(n)—SOR⁶, —(CH₂)_(n)—SO₂R⁶, —(CH₂)_(n)—SO₂NR⁶R⁷, or—(CH₂)_(n)—OR⁶; R¹² is selected from the group consisting of hydrogen,—CX₃, perfluoroalkyl, lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, —(CH₂)_(n)-heterocycle, and aryl; R¹³ is selected from thegroup consisting of hydrogen, —CX₃, perfluoroalkyl, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, —(CH₂)_(n)-heterocycle, and aryl; orR¹² and R¹³ may be linked together to form a 4-, 5- or 6-membered ringoptionally containing one or more hetero atoms selected from the groupconsisting of O, N, S, SO and SO₂, which may contain 1 or 2 doublebonds; and wherein ---- is a single or double bond; and n is0-4, or apharmaceutically acceptable salt thereof.